document resume - eric · document resume. se 047 486. research briefings 1986. for the office of...

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SE 047 486

Research Briefings 1986. For the Office of Scienceand Technology Policy, the National ScienceFoundation, and Selected Federal Departments andAgencies.National Academy of Sciences, Washington, D.C.National Science Foundation, Washington, D.C.ISBN-0-309-03689-586NSF-LDA850138270p.National Academy Press, 2101 Constitution Avenue,N.W., Washington, DC 20418 ($7.50).Reports - Descriptive (141)

MF01 Plus Postage. PC Not Available from EDRS.Artificial Intelligence; Atomic Structure; *Biology;Chemical Bonding; *Chemistry; *Decision Making;Disease Control; Engineering; *EngineeringTechnology; Government Publications; Heuristics;*Problem Solving; Research Needs; Science andSociety; Structural Analysis (Science);*Technological Advancement*Biotechnology; Proteins; Viruses

ABSTRACTThis is part of a series on selected areas of science

and technology prepared by the Committee on Science, Engineering, andPublic Policy, at the request of the Science Advisor to the Presidentof the United States. This volume includes four individual reports.The first is the report of the "Research Briefing Panel on Science ofInterfaces and Thin Films." It discusses the recent tools andtechniques that have become available for dealing with the scientificproblems of buried interfaces (the junction of two differentsubstances or two phases of the same substance). The second reportcomes from the panel dealing with decision making and problemsolving, presenting several theories and research opportunities inthose areas. The third panel's report deals with protein structureand biological function, citing recent advances in knowledge in thoseareas, including technological advances, and recommendations forfuture research. The last report in this document has to do with theprevention and treatmert of viral diseases. Recent advances inmolecular virology are discussed, along with specific strategies forpreventing viral diseases. (TW)

************************************************************************ Reproductions supplied by EDRS are the best that can be made ** from the original document. *********************************f.****************************t*********

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U 8 DEPARTMENT OF EDUCATIONOffice of Educational Research arid Improvement

EDUCATIONAL RESOURCES INFORMATION

XThisCENTER (ERIC)

document has been reproduced aseceived from the Persoh or organization

originating it.1:3 Minor changes have been made to improve

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Pointsof view or opinions stated m this doCu.ment do not necessarily represent officialOERI position or pat,/

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Ca MATERIAL IN MICROFICHE ONLYHAS SEEN GRANTED B

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TO THE EDUCATIONAL RESOURCESINFORMATION CENTER (ERIC)."

7.

ResearchBriefings

198for the Office of Science and Technology Policy,

the National Science Foundation,and Selected Federal Departments and Agencies

Committee on Science, Engineering,and Public Policy

National Academy of Sciences

National Academy of Engineering

Institute of Medicine

NATIONAL ACADEMY PRESSWashington. D.C. 1986

3

National Academy Press 2101 Constitution Avenue, NW Washington, DC 20418

NOTICE: The National Academy of Sciences was established in 1863 by Act of Congressas a private, nonprofit, self-governing membership corporation for the furtherance ofscience and technology for the general welfare. The terms of its charter require theNational Academy of Sciences to advise the federal government upon request within itsfields of competence. Under this corporate charter, the National Academy of Engineeringand the Institute of Medicine were established in 1964 and 1970, respectively.

The Committee on Science, Engineering, and Public Policy is a joint committee of theNational Academy of Sciences, the National Academy of Engineering, and the Instit-uteof Medicine. It includes members of the councils of all three bodies.

This woe., was supported by the National Science Foundation under Grant LDA8501382.

Library of Congress Catalog Card Number 86-61856

International Standard Book Number 0-309-03689-5

Copyright it 1986 by the National Academy of Sciences

No part of this book may be reproduced by any mechanical, photographic, or electronicprocess, or in the form of a phonographic recording, nor may it be stored in a retrievalsystem, transmitted, or otherwise copied for public or private use, without written per-mission from the publisher, except for purposes of official use by the United Statesgovernmcnt.

First Printing, July 1986Printed in the United States of America Second Printing, September 1986

Committee on Science,Engineering, and Public Policy

GILBERT S. OMENN, Dean, School ofPublic Health and CommunityMedicine, University of Washington,Seattle, Wash. (Chairman)

H. NORMAN ABRAMSON, ExecutiveVice-President, Southwest ResearchInstitute, San Antonio, Tex.

FLOYD E. BLOOM, Director andMember, Division of Pre-ClinicalNeuroscience and Endocrinology,Scripps Clinic and Research Foundation,La Jolla, Calif.

W. DALE COMPTON, Senior Fellow,Nation4 Academy of Engineering,Washington, D.C.

EMILIO Q. DADDARIO, Wilkes, Artis,Hedrick and Lane, Attorneys at Law,Washington, D.C.

GERALD P. DINNEEN, Vice-President,Science and Technology, Honeywell,Inc., Minneapolis, Minn.

RALPH E. GOMORY, Senior Vice-President and Director of Research,Thomas J. Watson Research Center,IBM Corporation, Yorktown Heights,N.Y.

*Terra expired June 30, 1986.

ZVI GRILICHES, Professor of Economics,Harvard University, Cambridge, Mass.

ARTHUR KELMAN, Wisconsin AlumniResearch Foundation Senior ResearchProfessor of Plant Pathology andBacteriology, Department of PlantPathology, University of Wisconsin,Madison, Wis.

*PHILIP LEDER, John Emory AndrusProfessor and Chairman, Department ofGenetics, Harvard Medical School,Cambridge, Mass.

FRANCIS E. LOW, Institute Professor,Department of Physics, MassachusettsInstitute of Technology, Cambridge,Mass.

EDWARD A. MASON, Vice-President,Research, Amoco Corporation, AmocoResearch Center, Naperville, Ill.

*DANIEL NATHANS, Professor,Department of Molecular Biology andGenetics, Johns Hopkins UniversitySchool of Medicine, Baltimore, Md.

JOHN D. ROBERTS, Institute Professor ofChemistry, Gates and CrellinLaboratories of Chemistry, CaliforniaInstitute of Technology, Pasadena,Calif.

KENNETH J. RYAN, Kate Macy LaddProfessor of Obstetrics and Gyne-ology,Harvard Medical School, and Chairman,Department of Obstetrics andGynecology, Brigham and Women'sHospital, Boston, Mass.

LEON T. SILVER, William M. KeckFoundation Professor of Geology,Division of Geological and PlanetarySciences, California Institute ofTechnology, Pasadena, Calif.

HERBERT A. SIMON, Professor ofComputer Science and Psychology,Department of Psychology, Carnegie-Mellon University, Pittsburgh, Pa.

*F. KARL WILLENBROCK, Cecil H.Green Professor of Engineering, Schoolof Engineering and Applied Sciei:.e,Southern Methodist University, Dallas,Tex.

*Term expired June 30, 1986.

vi

Ex Officio

FRANK PRESS, President, NationalAcademy of Sciences

ROBERT M. WHITE, President, NationalAcademy of Engineering

SAMUEL 0. THIER, President, Instituteof Medicine

COSEPLIP Staff

ALLAN R. HOFFMAN, Executive DirectorBARBARA A. CANDLAND,

Administrative CoordinatorJOANNA MASTANTUONO, Senior

Secretary

Preface

Research Briefings 1986 is the fifth volumeof research briefing reports on selected areasof science and technology prepared by theCommittee on Science, Engineering, andPublic Policy (COSEPUP).* The briefings areprepared at the request of the President'sScience Advisor, who also serves as Directorof the White House Office of Science andTechnology Policy (OSTP), and the Directorof the National Science Foundation (NSF).

The four individual reports in this volumebring to 32 the number of such reports de-veloped by COSEPUP. A list of the subjectscovered in Research Briefings volumes eachyear since 1982 is appended to this preface.Together they constitute a rich set of as-sessments of recent advances and high-leverage research opportunities in a largenumber of critical fields of science and tech-nology.

In addition to their collective value, in-dividual briefing reports have had signifi-cant impact in their respective fields. For

"COSEPUP is a joint committee of the National Acad-emy of Sciences, the National Academy of Engineer-ing, and the Institute of Medicine, which together areknown as the National Academy complex.

vii

example, Dr. George Keyworth II (Presi-dential Science Advisor when the briefingswere initiated) has noted that the researchbriefing on Computers in Design and Man-ufacturing "led almost directly and quicklyto an important new program of Engineer-ing Research Centers in the National Sci-ence Foundation." Other research briefingshave influenced federal priorities and fund-ing in mathematics, astronomy and astro-physics, plant sciences, and the solid earthsciences. Often, briefings have highlightedinterdisciplinary connections, as in neuro-science, materials science, cognitive scienceand artificial intelligence, and biotechnol-ogy. Clearly, the research briefing activityhas become an important new means of co-operation between the federal governmentand the National Academy complex.

As it has evolved through five annualrounds, the research briefing activity in-volves, first, the selection of topics by theOSTP and NSF directors in response to sug-gestions offered by COSEPUP. The brief-ings are then developed by panels of expertscharged with assessing the status of the fieldand identifying those research areas withinthe field likely to return the highest scientificdividends as a result of near-term federal

investment. COSEPUP then reviews thebriefings before their presentation in oraland written form to officials in the WhiteHouse, the National Science Foundation,other executive branch departments andagencies, and the Congress. The briefing re-ports, which are published and made widelyavailable by the National Academy Press,are used in evaluations of the state of U.S.science and technology and in developmentand review of budget proposals.

Development of the briefings depends onthe cooperative efforts of many: the scien-tists and engineers who serve in a vAonteer

capacity on the panels; those in the ScienceAdvisor's office and the National ScienceFoundation who provide guidance and sup-port throughout the process; and the Na-tional Academy complex staff who recom-mend potential topics and whose dedicatedefforts facilitate the day-to-day activities ofthe briefing panels. To all, COSEPUP ex-presses deep appreciation and sincere thanks.

Gilbert S. Omenn, ChairmanCommittee on Science, Engineering,and Public Policy

RESEARCH BRIEFING TOPICS*

/9861. Science of Interfaces and Thin Films2. Decision Making and Problem

Solving3. Protein Structure and Biological

Function4. Prevention and Treatment of Viral

Diseases

1985

1. Remote Sensing of the Earth2. Pain and Pain Management3. Biotechnology in Agriculture4. Weather Prediction Technologies5. Ceramics and Ceramic Composites6. Scientific Frontiers and the

Superconducting Super Collider7. Computer Vision and Pattern

Recognition

/9841. Computer Architecture2. Information Technology in Precollege

Education3. Chemical and Process Engineering

for Biotechnology4. High-Performance Polymer

Composites

"The reports listed here are published in Research Brief-ings 1986, Research Briefings 1985, etc., by the NationalAcademy Press, Washington, D.C. viii

1984 (Continued)

5. Biology of Oncogenes6. Interactions Between Blood and

Blood Vessels (Including the Biologyof Atherosclerosis)

7. Biology of Parasitism8. Solar Terrestrial Plasma Physics9. Selected Opportunities in Physics

1983

1. Selected Opportunities in Chemistry2. Cognitive Science and Artificial

Intelligence3. Immunology4. Solid Earth Sciences5. Computers in Design and

Manufacturing

1982

1. Mathematics2. Atmospheric Sciences3. Astronomy and Astrophysics4. Agricultural Research5. Neuroscience6. Materials Science7. Human Health Effects of Hazardous

Chemical Exposures

Contents

Report of the Research Briefing PanelInterfaces and Thin Films

Report of the Research Briefing Paneland Problem Solving

Report of the Research Briefing Paneland I3iological Function

Report of the Research Briefing Paneland Treatment of Viral Diseases

ix

on Science of

on Decision Making

on Protein Structiire

on Prevention

1

17

37

49

Report of theResearch Briefing Panel on

Science of Interfaces and Thin Films

Research Briefing Panel onScience of Interfaces and Thin Films

John A. Armstrong (Cochairman), IBMCorporation, Yorktown Heights, N.Y.

George M. Whitesides (Cochairman),Harvard University, Cambridge, Mass.

John H. Birely, Los Alamos NationalLaboratory, Los Alamos, N.Mex.

Peter R. Bridenbaugh, ALCOA TechCenter, Alcoa Center, Pa.

Norman Gjostein, Ford MotorCorporation, Dearborn, Mich.

Arthur C. Gossard, AT&T BellLaboratories, Murray Hill, N.J.

Franz J. Himpsel, IBM Corporation,Yorktown Heights, N.Y.

N. J. Johnston, NASA Langley ResearchCenter, Hampton, Va.

Robert W. Mann, Massachusetts Instituteof Technology, Cambridge, Mass.

Thomas McGill, California Institute ofTechnology, Pasadena, Calif.

Calvin G. Quate, Stanford University,Stanford, Calif.

2

Dotsevi Y. Sogah, E. I. du Pontde Nemours & Company, Inc.,Wilmington, Del.

Mark Wrighton, Massachusetts Institute ofTechnology, Cambridge, Mass.

Staff

William Spindel, Project Director,Commision on Physical Sciences,Mathematics, and Resources

Robert M. Simon, Staff Officer,Commission on Physical Sciences,Mathematics, and Resources

Alfred B. Bortz, ConsultantSandra Nolte, Senior SecretaryAllan R. Hoffman, Executive Director,



Science of Interfaces and Thin Films

DEFINITIONS, PROPERTIES, ANDBEHAVIORS

A thin film is matter of microscopic thick-nesstypically, only a few atoms to a fewthousand atoms. Its extent in its other twodimensions is macroscopic. An interface isthe junction of two different substances ortwo phases of the same substance. Theproperties of these quasi-two-dimensionalentities are often remarkably different fromthe properties of bulk matter of the samecomposition.

Thin films and interfaces are associatedconcepts. Thin films (for example, the iri-descent film that forms when oil floats onwater) are familiar. Interfaces are less fa-miliar, although ubiquitous; they occurwherever different homogeneous phasesmeet. For examp!e, the oil film on water hastwo interfaces: one with water and one withair. As the thickness of a film decreases, itsproperties are increasingly determined byits interfaces. At the limit of thinness, thinfilms and interfaces merge. An interface canbe thought of as a film so thin it has nohomogeneous interior; a thin film is a sys-tem whose interior is strongly influenced bythe close proximity of its interfaces.

3

The current interest in thin films and in-terfaces reflects both timely opportunities inbasic science and importance and perva-siveness in technology.

A broadly important problem in scienceis that of the basic relations between themacroscopic properties of matter (e.g.,wettability, electrical and thermal conduc-tivity, hardness, reflectivity) and its atomic-level structure. Because the detailed struc-tures of interfaces and thin films can be ma-nipulated with greater control than can thoseof bulk solids or liquids, they provide par-ticularly attractive systems for studying thesebasic relations.

A number of interesting phenomenaespecially manifestations of quantum be-havioronly appear in small systems. Thinfilms and interfaces can be of a size thatdisplays these phenomena. Thus, for ex-ample, the rate of transport of electronsacrossthin films by quantum tunneling may bevery high when the thickness of the filmsis comparable to the extension of electronicwave functions (10 to 100 angstroms).

The structure, properties, and reactivityof matter at an interface can be very differ-ent from those of matter in bulk because of

12

Figure 1 Schematic cross section of a drop ofwater spreading on a solid support. The exis-tence of a "precursor film," a thin lip of liquid(not drawn to scale) extending beyond the drop,is due to long-range interactions between thesolid and the liquid. SOURCE: Based on P. G.deGennes, Reviews of Modern Physics, Vol. 57,No. 3 (1985):827-863.

the close proximity of the interfacial matterto matter of different composition, or of theinterfacial matter to vacuum. Thus, goldatoms at a gold-silicon interface do not be-have like gold atoms in bulk because manyof their nearest neighbors are silicon atoms;gold atoms at a gold-vacuum interface be-have differently from those in bulk becausethey lack the complement of near neighborspresent in a solid.

The connections between science andtechnology are particularly close and usefulin matters concerning thin films and inter-faces. Technologically important physicalpropertiesstrength, corrosion resistance,biocompatibilityare often determined bythe characteristics of thin films and inter-faces.

An interface can be the exposed atomson the exterior of a metal single crystal invacuum, the junction between a siliconsubstrate and a silicon dioxide overlayer,the boundary between phase-separatedblock copolymers, the junction between afiber and polymer matrix in a compositeaircraft part, or the region of contact be-tween blood and an implanted prosthesis.A thin film can be the membrane enclosinga living cell; the thin layers of conductors,semiconductors, and insulators that con-stitute a microelectronic device; the lay-ered media of a magnetic informationstorage disk; the layers used for lubrica-tion, adhesion, and passivation; or thecoatings of surfactants that are used to sta-bilize suspensions. The properties of these

4

thin films depend strongly on their con-stituent interfaces.

The examples that follow illustrate severalinteresting and important characteristics ofmatter in two dimensions.

The presence of a solid in contact with liquidwater has a profound influence on the characterof the water. Figure 1 is a diagram of a smalldrop of water spreading on a solid. The cur-vature of the major part of the surface ofthe drop is determined by a balance of ener-gies at the liquid-vapor, liquid-solid, andsolid-vapor interfaces. A feature of greatcurrent interest is the so-called "precursorfilm," a lip of liquid a few hundred ang-stroms thick extending for microns beyondthe edge of the drop. Current explanationsof this precursor film attribute its existence,at least in part, to long-range interactionsbetween the liquid and the solid surface.The strength of these interactions is suffi-cient to pull a thin film at the edge of thedrop flat against the surface. Electrochem-ical evidence supports a model for waternext to an interface that is qualitatively dif-ferent from bulk water: interfacial water mayhave a dielectric constant as low as 30 (thedielectric constant of bulk water is 78). Un-derstanding the behavior of liquid-solid in-terfaces is critical to understanding wetting,and thus to such technologies as adhesionand corrosion protection.

Matter in thin films may exhibit phase be-havior that is quite different from the phase be-havior the same matter exhibits in bulk. A systemcomposed of krypton that is adsorbed on

13

SCIENCE OF INTERFACES AND THIN FILMS

graphite at a pressure and temperaturesufficient to give a coverage of one to twomonolayers shows remarkably complexphase behavior. The krypton in the firstmonolayer is a fluid at 130K, the high endof the temperature range. As the temper-ature is lowered, the krypton first freezesinto a two-dimensional solid, then meltsinto a new fluid, and finally freezes againintc new solid. The structures of the solidphases exhibited by this system have beencharacterized (see Figure 2). In the higher-temperature solid phase, the krypton atomsposition themselves in a low-density crys-tal in register with the underlying graphitelattice. This structure is dominated bykryptoncarbon interactions; and in it, thekrypton atoms are spaced slightly beyondhard-sphere contact. In the lower-temper-ature solid, krypton condenses to a high2r

density in the first monolayer and crys-tallizes in a structure dominated by kryp-tonkrypton interactions; in this structure,the registration with the graphite lattice isdestroyed. This system illustrates the del-icate balance between forces among thekrypton atoms in an adsorbed monolayerand between these atoms and the graphitesubstrate on which they are adsorbed.Studies such as this of krypton on graphiteestablish the ability of current instrumen-tal techniques to characterize the struc-tures of monolayers; they also provide astarting point for studying the thermo-dynamics of thin films. Although inert gassystems are of limited practical interest,they are the simplest systems to analyzetheoretically, and they provide conceptualmodels for systems dominated by weakatomatom interactions.

5

Figure 2 Krypton adsorbed on graphite. A low-density crystalline phase (upper diagram) isdominated by kryptongraphite interactions: thekrypton atoms are placed slightly beyond hard-sphere contact. The high-density crystallinephase (lower diagram) brings the krypton atomsinto contact but destroys the registration withthe underlying graphite lattice. SOURCE: Basedon R. J. Birgeneau and P. M. Horne, Science 232(1986):329.

14

Bulk and interfacial electrical and magneticproperties of materials may be strikingly differ-ent. Bulk crystalline silicon is a semicon-ductor; the interface of a silicon crystal cutto expose a particul ir crystal plane, the Si(111)face, exhibits metallic behavior. This phe-nomenon is not yet understood theoreti-cally, but a critical first stepestablishingthe structure of the Si(111) interfacehasbeen taken recently through the use of scan-ning tunneling microscopy. The observedstructure shows significant changes in atomicpositions relative to bulk; some bond anglesare different.

Far from being passive containers for thecontents of the cell, the membranes covering cellsare highly organized, dynamic, structurally com-plex biological systems that regulate communi-cation between matter lying inside and outsideof the cells. One important constituent of cellmembranes is a class of molecules, the phos-pholipids, that spontaneously forms bilayerfilms in a number of geometries. Many ofthe important physical properties of cellmembranes, such as two-dimensional dif-fusion and differentiation between the "in-side" and "outside" of biological entitiesshaped like a tube or sphere, can be studiedusing these spontaneously formed struc-tures.

The characteristic chemical reactivities of metalatoms at the exposed interface of bulk metal andof small metal clusters provide the basis for het-erogeneous catalysis. Heterogeneous catalysis(that is, catalysis using solid catalysts) is animportant technology for the production offuels and chemicals. The metal atoms usedin a heterogeneous catalyst are chosen fortheir high reactivity. As a result of their lo-cation in a soLid interface, they are simul-taneously accessible to reactants in acontacting vapor or liquid and isolated fromreaction with one another.

Microelectronic devices are assemblies of thinfilms; many of the properties of these devices de-rive from the special properties of electrons in thefilms and the transport of electrons in and acrossthe interfaces joining them. Figure 3 is a sche-

matic cross section through one part of sucha device: a multilayer system connecting atransistor to make ohmic contact to a solderpad. The conductors in this system are 0.1to 5 micrometers (1,000 to 50,000 angstroms)in cross section; in operation, they can carrycurrent densities of up to 105 amps/cm2. Theforce of this "electron wind" is sufficient tocause electromigration, or migration of atomsin the conductors from their normal latticesites. Remarkably, some of these atoms mi-grate with the wind, and some migrateagainst it. The basis of this phenomenon isincompletely understood, but its originclearly lies in the small size of the conduc-tors; its control is important in reducing thesize of integrated circuit chips.

Insertion of a monolayer, 20 angstroms thick,of a simple organic substancehexadecylamine,CH3(CH2)15NH2between two steel surfaces insliding contact reduces the friction between thenzby a factor of 10. This reduction in frictionreflects spontaneous formation of an or-dered film of the organic species: the amine(NH2) groups bond to the metal, and thehydrocarbon chains orient roughly perpen-dicular to it. The film is thus a thin hydro-carbon liquid or liquid crystal bonded to themetal, a material that resists the transitoryadhesion between the metal pieces that con-tributes strongly to friction. Understandingthe details of the relations between thestructure of the adsorbing organic mole-cules, the solid phase on which they adsorb,and the structure and properties of thesetypes of spontaneously self-organizingmonolayer films promises to stimulate thedesign of thin-film systems to control fric-tion, wear, corrosion, and adhesion.

In short, matter present in thin films orat interfaces can exhibit unique properties.Understanding and controlling these prop-erties have been difficult because of the smallquantities of material present in most inter-faces and thin films relative to the bulk, andbecause many of the interfaces of greatestinterest are "buried" inside solids or under

6

15


Pb-Snsolder pad Cu-Sn intennetallic

Phased Cr.Cu

Cr

2.8 pm S102

3.8 pm S102

2.3 pm A1-4% Cu

0.8.1 tun A1.4% Cu

2.4 pm SiO2

1.4 mA. o u

S13N4 Thermal SiO(' PtSi-".'0.15 pm Cr.Crpy

liquids. New instrumental techniques com-bined with theory and computer modeling,however, enable us to define the structuresof many interfaces. With sound structuralinformation and new methods of prepara-tion, it is now possible to explore the richphenomenology of interfaces and thin films.

RESEARCH ISSUES

CHARACTERIZATIOI, INTERFACES ANDTHIN FILMS

The bonding characteristics and electronicstructure of most interfaces (even the "sim-ple" solidvacuum interfaces of crystallineelements) are still poorly understood, andno technique for establishing these struc-tures is universally applicable. (The struc-ture of an interface cannot necessarily beextrapolated from that of the underlying bulksolid.)

Much of the information about the struc-tures of interfaces has come from forms ofspectroscopy that are limited to solidvac-uum interfaces, but emerging techniques cannow characterize solidgas and solidliquidinterfaces. The most exciting of these tech-niques is scanning tunneling microscopy, orSTM (Figure 4). STM measures the very smallcurrent that flows when a potential is ap-

7

Figure 3 Sectional drawing of multilevel in-terconnections for advanced bipolar devices.SOURCE: L. J. Fried et al., IBM Journal of Re-search and Development 26 (3 May 1982).

plied between a conducting interface and aprobe tip (only a few atoms in size) scannedacross the interface at a distance of ang-stroms. The current is caused by quantumtunneling of electrons between individualatoms on the interface and on the probe,and it is extremely sensitive to the distancebetween the atoms. This remarkable devicemakes it possible to observe individual atomson irregular interfaces. STM is being usedto study interfaces in contact with insulatingliquids; it is applicable to noncrystalline sol-ids; and it can be used to examine dynamicprocesses occurring at inter! .ces. It shouldbe particularly useful in examining thestructures of individual defects on inter-faces.

A second instrument relying on the abilityto position interfaces with angstrom-scalecontrol is the interface force balance. This de-vice holds two flat solids (for example, sheetsof inica) at accurately known separations offrom 3 to 500 angstroms, and measures theattraction or repulsion between them. Themeasurements can be carried out with thesolids separated by vacuum, gas, or liquid,or with the solids carrying monolayers ofother materials bonded or adsorbed to theirinterfaces. The measurements make possi-ble direct analysis of the forces responsiblefor interactions between interfaces, modi-fication of these forces by intervening con-

Figure 4 Scanning tunneling microscopy spec-troscopya topograph of an Si(111) 7 x 7 sur-face. By changing the voltage, one is able tomeasure electrork states within an area of atomicdimensions. Defects (some of which show upas extra dark spots in the topograph) can alsobe probed by this method. SOURCE: J. E. De-muth et al., IBM Corporation.

densed phases, and, by inference, interactionof the interfaces with the condensed phases.

A selection of the wide range of other in-strumental techniques now being used tocharacterize interfaces is presented in Table 1.The sheer Aumber of available techniquespresents interface science with both an op-portunity and a problem. The techniquesprovide many useful ?.tid complementarytypes of information; but because no singletechnique uniquely characterizes any sys-tem, it is necessary for an effective labora-tory to have access to several instruments.Their expense and complexity in turn raisea substantial problem in management forsmall research giuups.

Current objectives of research in struc-tural aspects of interface science are the de-velopment of techniques for characterizingburied interfaces (for example, grain bound-aries in metals and ceramics, the fiberma-trix interface, and defects in composites);and for examining electrically insulating in-terfaces such as those on organic polymers.

PREPARATIVE TECHNIQUES

One objective of current research is thedevelopment of techniques for producinghighly perfect, smooth, single-crystal films.

8

A number of techniques are used for prep-aration of electronic materials, ranging fromsimple vacuum evaporation to molecular beamepitaxy (MBE) and metal-organic vapor phaseepitaxy (MOVPE). (Epitaxy is the growth ofa crystalline film of one material on a crystalface of a second in such a way that the crys-talline orientation of the deposited materialfollows that of the substrate.) Current sci-entific understanding of the processes un-derlying all these techniquesprocesses thatinclude the movement of species on the in-terfaces, mechanisms of ;;nnealing and re-lief of stress, incorporadon of impurities,nucleation and growth of defectsis lim-ited; an improvemer t in that understandingwould be immensely valuable in technol-ogy.

Epitaxial growth techniques seem certainto be particularly useful. They can be usedto make very small structures such as quan-tum wells (structures whose composition istailored at angstrom scales to control elec-tronic energy levels); films with extraordi-narily high electron and hole mobilities; andtransistors, lasers, and magnetic materialsthat are capable of record-setting perfor-mances.

The most interesting strategies for prep-aration of thin films of organic constituents

1 7


are based on the spontaneous self-assemblyof low molecular weight molecules at inter-faces. For example, so-called Langmuir-Blodgett monolayers are formed by spread-ing an organic substance such as stearic acid(CH3[CH2116CO2H) at the interface betweenair and water. The hydrophilic CO2H groupsare attracted to the water, while the hydro-phobic hydrocarbon chains are exduded fromit. When the surface film is compressed, theorganic molecules pack as a two-dimen-sional crystal or liquid crystal that can betransferred intact to a solid support. Similarfilms can be formed in many cases by simplyallowing the organic substance to adsorb fromsolution onto a support: the desired order-ing occurs spontaneously. These techniquesmake it possible to prepare macroscopic, two-dimensional, organic monolayer films whilemaintaining a high degree of control overthe nature of the exposed surface functionalgroups, the order of the films, and (to amore limited extent) their physical and me-chanical properties. These systems are ex-ceptionally attractive as substrates for thestudy of relationships between interface

structure and such properties as wettability,biocompatibility, electrical resistivity, andnonlinear optical response.

PROPERTIES OF MATTER IN Two DIMENSIONS

The quasi-two-dimensional geometry ofinterfaces and thin films, and the high gra-dients in properties across them, can wsultin unique properties for matter in these sys-tems. Of the wide range of topics that mightbe used to illustrate the characteristic prop-erties of interfaces and thin films, devicephysics offers a particularly clear demon-stration of the interplay between science andtechnology. The use of thin films is impor-tant in the construction of devices for tworeasons: (1) small size permits a high den-sity of devices, thus minimizing power con-sumption and maximizing speed; and(2) small size is required for many devicesthat exploit quantum effects.

A two-dimensional electron gas exists atthe interface between the silicon channel andgate insulator in metal oxide semiconductor(MOS) devices; similar electron gases are

TABLE 1 Selected Spectroscopic Techniques Applicable to Interfaces

Technique (Acronym) Application

Scanning tunneling microscopy (STM)Neutron scatteringLow-angle x-ray scatteringSurface-enhanced Raman spectroscopy (SERS)

X-ray photoelectron spectroscopy (XPS); Augerspectroscopy

High-resolution electron microscopy

Rutherford backscattering (RBS)

Secondary ion mass spectroscopy (SIMS)Reflectance infrared spectroscopy

Acoustic microscopyNuclear magnetic resonance spectroscopy (NMR)Electron paramagnetic resonance spectroscopy

(EPR)

Individual atomic positions on surfacesStructures of crystalline surfaces;

surface morphologyVibrational spectroscopy of adsorbates on small

metal particlesElectronic structure of atoms in the top 10

angstroms of an interfaceA wide variety of information concerning structure,

composition, and morphology; single atomimaging in special cases

Atomic composition as a function of depth withresolution of hundreds of angstroms

Molecular-sized fragments of interfacesVibrational and structural analysis of organic thin

filmsInterface structures at the 10,000 A levelInterface structures at tlYe 10,C00 A levelParamagnetic centers in interfaces

9

18

important in many other types of devices.The transport properties of these two-di-mensional electron gases exhibit a numberof new phenomena: for example, negativeresistance, in which current decreases withincreases in applied voltage because of elec-tron tunneling into energy sub-bands withlower momentum; and ballistic transport, inwhkh electrons move without phonon scat-tering in structures with very sma'l dimen-sions. Heterojunctions (structures involvingan interface between two different semicon-ductors) are the basis for a number of de-velopments in device physics. New light-emitting structures involving multiple het-erojunctions (so-called quantum-well lightemitters) provide light at wavelengths pre-viously unattainable. Super lattices formed byproducing a series of periodically spacedheterojunctions are materials with new non-linear optical and magnetic properties.

INTERFACE REACTIVITY

Atoms and molecules present at an inter-face can experience a highly anis )tropic en-vironment with characteristics that aredifferent from surrounding bulk phase(s).The chemical reactivity of a species presentat an interface may, in consequence, be dif-ferent from the reactivity of the same speciespresent in an isotropic phase.

As one example, aggregates of platinumatoms supported on alumina react with hy-drocarbons in ways that depend strongly onthe size and shape of the metal aggregate,on the acidity of the underlying aluminasupport, and on the nature of the interactionbetween the aggregate and the support.Platinum atoms are intrinsically highly re-active toward hydrocarbons. But platinumatoms in bulk platinum are not accessible;hence, they are not active catalytically. Plat-inum atoms in solution tend to react indis-criminately with one another, with speciesused to increase their solubility, and withthe intended reactants. Small aggregates ofsupported platinum thus provide systems

10

in which a high proportion of the platinumis stably isolated and exposed at an inter-face, available for reaction. In these sys-tems, the reactivity of the platinum can alsobe tailored to favor useful reactions bychanging the underlying support. The reac-tivity toward hydrocarbons of platinum,.upported on alumina forms the basis forone of the critical steps in petroleum refin-ing.

A second example is the unexpected ac-idities of organic functional groups presentat the interface between '.(YW dielectric poly-mers, such as polyethylene, and water. Theapparent acidity of a carboxylic acid (CO2H)group at such an interfacethat is, the con-centration of protons in solution at whichthese groups are half-ionized to carboxylateions (C0i")is shifted by 106 from thatcharacterizing the same groups in homo-geneous aqueous solution. The shift in ap-parent acidity reflects three factors: (1) thelow local dielectric constant at the polymerwater interface; (2) the anomalously low po-larity of the water present at this interface;and (3) electrostatic interactions at the sur-face. The unexpected reactivity of functionalgroups present at polymerfluid interfacesis clearly relevant to wetting of and adhe-sion to polymers, and to other processesinvolving the reaction and solvation of func-tional groups present in polymer interfaces.It is also relevant to the characteristics offunctional groups present at many other in-terfaces, especially those between water andsuspensions, micelles, and proteins.

BIOCOMPATIBLE SURFACES AND INTERFACES

A biomaterial is any substance or devicewhose function depends on contact with abiological medium. Thin films and inter-faces play an essential role in the design andfunction of the numerous implants and de-vices that are now being used clinically. Theirsurfaces induce deposition of pro eins,platelets, and other cellular elements, and

19


often induce platelet aggregation and bloodclot (thrombus) formation.

Although functional aspects of the per-formance of artificial materials in the humanbody can be predicted with some reliability,forecasting their biologkal performance isdifficult. Fundamental information on thecorrelation between the in vivo and in vitroresponses is limited. An understanding ofthe dynamic biological changes occurring atthe materialtissue interface is necessary topredict biological performance. For practicalapplication, factors influencing interactionsof blood with materials and biological sur-faces are particularly important. We mustlearn how these interactions are affected bysurface morphology or by specific chemicalgroups on the surface, and what influenceis exerted by the mechanical properties ofthe interface.

APPLICATIONS

MICROELECTRONICS IN COMMUNICATIONSAND COMPUTERS

Microelectronic technologies are foundedlargely on structures composed of thin filmsand interfaces. The silicon-based semicon-ductor industry depends critically on the stillincompletely understood interface betweensilicon and insulators such as silicon dioxideand silicon nitride. Lasers, detectors, andnew high-speed devices use heterojunc-tions in which the interface is the key activecomponent. The conduction of electricity inmicrofabricated devices requires reproduc-ible interfaces between metallic conductorsand the active semiconducting layer, the so-called ohmic contact. Such contacts becomeincreasingly difficult to establish as dimen-sions decrease. Mass storage technologies(magnetic disks, optical and magneto-opti-cal storage devices, magnetic bubble mem-ories) depend on films that are only hundredsof angstroms in thickness but that are uni-form over many square centimeters.

11

Packaging and interconnect technologiesare as important as chip technologies to fu-ture developments in high-performancecomputing systems. Processing speeds areoften limited by the time required to prop-agate information from one chip or subsys-tem to another, and the fabrication andassembly of very small systems is crucial inbuilding high-speed computers. Of neces-sity, the components in these systems aredensely packed, and they may generate largequantities of heat whose removal is con-trolled by interfacial thermal conductivity.

Long-term objectives include the devel-opment of systems that allow direct con-nection of electronic devices to biologicallybased sensors or to nerves. Both require thesolution of substantial problems in interfacescience. Another challenging interfacialproblem is the development of practicaltechniques that interconvert electrons (thecurrency used by digital devices) and neu-rotransmitters (the currency used by nerves)to permit the nondestructive stimulation orsensing of nerve impulses.

CONTROL OF CORROSION, FRICTION,AND WEAR

Corrosion is the result of electrochemicalprocesses occurring at interfaces betweenmetal and water and air. Control of corro-sion is usually achieved by the applicationof thin protective films to the metal inter-face. Although techniques for corrosioncontrol are highly developed empirically, toooften they are effective only for short peri-ods, and their fundamental basis is oftenobscure. Studies of the formation, thermo-dynamic and kinetic stability, and barrierproperties of thin films on metals are nowpossible at levels of detail that will be in-creasingly useful in developing new strat-egies for control of corrosion.

The practice of lubrication has developedadequate engineering models for elastohy-drodynamic lubrication (EHL), provided thelubricant is present as a thick film and be-

20

haves as a Newtonian fluid. As the thick-ness of the lubricant film approachesmolecular dimensions, as in asperity con-tact, pressures become high, approaching1 gigapascal; shear forces become very high;and lubricants solidify, crystallize, and de-grade. Many lubricated surfaces are coveredwith softer adherent films derived at leastin part from the lubricant; these :1113 mitigate asperity contact when forces exceedthe EHL limit. Understanding thin lubricantand adherent films, espedally under the ex-treme conditions of asperity contact is nowconceivable, although still difficult.

Controlling wear at the headmedium in-terface in a high-density magnetic storagedevice provides an example c f a currentproblem in this technology. The thin-film.magnetic recording medium on a disk is partof a multilayer structure. It is protected byanother thin filma wear-resistant over-coatthat may, in the future, be a dia-mondlike carbon. The magnetic medium maybe bonded to its substrate by yet anotherthin film, and there may be a magnetic un-derlayer. In Winchester hard disk technol-ogy, a microfabricated head literally flies overthe disk, supported by an air bearing whosewidth is comparable to the average distancebetween collisions of individual moleculesin ambient air (-900 angstroms). Efforts toincrease the density of data storage requirecloser head/disk spacings; they also raiseformidable problems in lubrication, "stic-tion" (adhesive effects of the lubricant dur-ing static head/disk contact), wear, adhesion,and delamination.

STRUCTURAL MATERIALS

Interfaces play a central role in determin-ing the mechanical properties of a range ofstructural materials, among which are fiber-reinforced composites, metals, and ceram-ics. In broad terms, the failure of structuralelements almost always involves inelasticdeformation and fracture. The atomisticsthe details of kinetics and thermodynam-

12

icsof the processes involved in initiationand propagation of cracks in a material un-der strain, and the processes that protectagainst fracture (dissipation of energythrough the creation of dislocations, for-mation of cracks and voids, and other mech-anisms) are various and incompletelyunderstood. But they all have as a commonresult e formation or alteration of inter-faces.

Fiber-reinforced composites consist of anordered dispersion of fibers in a polymermatrix. The fibers provide stiffness andstrength; the matrix distributes the loadamong the fibers and protects them fromdamage. The large area of interface con-necting fiber and matrix makes a critical con-tribution to the mechanical properties of thematerial. Failure often involves these inter-faces (Figure 5), but the relationship be-tween their structure and mechanicalperformance is poorly understood. Howtightly should the fiber and the matrix ad-here to achieve optimal performance? Whatmechanical properties in the interface bestdissipate energy during incipient failure?How should the optimum interface be pre-pared? What is the proper surface chemistryfor the fiber, and how should the fiber bebrought into contact with the matrix? An-swers to these questions would provide thebasis for rational optimization of compositesystems and would be of substantial valueto users of composites, especially in the au-tomotive and aircraft industries.

ENERGY PRODUCTION

Chemically active interfaces are required asheterogeneous catalysts in the refining ofpetroleum. Corrosion-resistant interfaces areneeded in the heat transfer systems of powerplants.

Fuel cells and certain kinds of batteriescan be substantially improved by new cata-lytic electrodes that will allow more efficientuse of atmospheric oxygen. The reductionof oxygen by electrons to water is slow at

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Figure 5 Fractured surface of a polymeric composite: unsized chopped carbon fibers in a polycarbonate matrix.SOURCE: NASA Jet Propulsion Laboratory.

conventional electrodes, and even the bestplatinum catalysts have rates that give out-put voltages that are only one-half of whatis theoretically possible. The inefficiencyof these catalysts is not intrinsic to all sys-tems that reduce oxygen; in biological sys-tems, through molecular mechanisms thatare still incompletely understood, the re-duction of oxygen to water takes place rap-idly. Recent experiments with syntheticcatalysts have demonstrated the reductionof oxygen to water without the use of plat-inum, but substantial improvements in thelifetime and cost of electrode-confined ca-talysts must be achieved before the sys-tems are economical.

13

The production of petroleum illustratesanother important set of interfacial prob-lems. One of the approaches to increasingthe production of crude oil from partiallydepleted fields is to "launder" the oil-bear-ing rock using detergents similar to thoseused in cleaning oil-stained clothes. Watercontaining the detergents is pumped intothe reservoir; the detergent separates thepetroleum from the rock and permits it topass through fine pores in the rock.

Currently, the economic feasibility of de-tergent-based methods for oil recovery re-mains unclear for most oil fields; it has proveddifficult to find detergent mixtures that areinexpensive, effective, and stable in the res-

22

ervoir. Designing successful detergents willrequire a detailed knowledge of the rela-tions between their structures and the waysin which they modify the properties of oil-water interfaces.

NATIONAL SECURITY

Many of the arylications of interface andthin-film technology in military and civiliansystems are similar, with the important dif-ference that military systems must functionin extremely demanding environments withvery high standards of performance. A fi-ber-reinforced composite wing for a militaryaircraft is subjected tc greater stress than asimilar wing on a civilian aircraft; therefore,optimization of the fiber-matrix interface iscorrespondingly more important. Becausean engine for a tank operates much closerto its limits of failure than a comparable en-gine for a civilian truck, the design of criticalcomponents such as bearings requires bet-ter control of interfaces to minimize frictionand wear.

There are also, however, certain areas oftechnology in which military requirementsare unique. Interfaces are critical whereverhigh electromagnetic fields interact withmatter. Mirrors for high-powered lasers mustbe immune to optical damage, and interfa-cial phenomena play a dominant role in de-termining their damage thresholds.Multi layer structures composed of alternat-ing thin films of refractory metals and di-electrics are important for x-ray optics. High-powered accelerators operate with very highsurface fields in their resonant cavities; thecomposition and morphology of the cavityinterfaces contribute both to the sharpnessof the resonant frequency and to the rate ofsurface heating during use. Certain militaryelectronics devices must resist damage by ra-diation; high speeds and low power con-sumption are also important. Promisingtechnologies to meet these requirements arebased on thin-film heterostructure devices.In addition, new thin-film coatings are

14

neeued that prevent the reaction of lithiumhydride and uranium with water vapor overintervals of decades. The stabilities of nucleardevices, an important element in the designof test ban treaties, are greatly influencedby interfacial reactivities.

MANAGEMENT ISSUES

Increased U.S. investment in the scienceof thin films and interfaces will produce alarge return in improved technology. Whatare the goals of an appropriate investmentstrategy? What are the management issuesraised by its execution?

1. Investment should build strong, two-way interactions between basic science andadvanced technology. Inefficient two-waycommunication between these two spheresis a major hindrance in the cycle of productdevelopment; because technological appli-cation of thin films and interfaces is only asmall step beyond basic research, researchresults will be invaluable to technologists.Unexplained and uncontrolled phenomenain technology, in turn, will stimulate basicresearch.

2. Investment should encourage interdis-ciplinary collaboration and join and exploitthe strengths of academic, industrial, andgovernment research and development in-stitutions.

3. An effective strategy should provideselected groups and/or institutions with asufficiently complete subset of the sophis-ticated analytical and preparative tools re-quired to conduct effective research in thinfilms and interface science. One possible in-stitutional structure would be researchgroups of about four faculty members thatwould focus on a coherent theme (for ex-ample, microelectronic interfaces, electroac-tive surfaces, or biocompatible materials).Each such group would manage a reason-able subset of preparative and analytical tools(see Table 1) that while possibly incompleteshould still be sufficient to carry out a major

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portion of the group's preparative and an-alytical work, supplemented by the use ofequipment in other locations.

4. The scale of modern surface and in-terface research falls in between "small" and"big" science; this intermediate size com-plicates issues in management. For exam-ple, although individual researchers are notforced (as is the case in experimental high-energy physics) into large collaborativeprojects with explicit management struc-tures, the single principal investigator, withhis specialized technique or knowledge, sel-dom has adequate resources to solve com-plex experimental problems.

5. Personnel Requirements. Too fewtrained students are being produced in someimportant areas of interface research. For

15

example, although there are many well-trained students in compound semicon-ductor interface science, there are compar-atively few in such areas as polymer-metal,polymer-carbon, and polymer-ceramic in-terfaces; silicon epitaxial growth; colloid sci-ence; and biocompatible surfaces.

In summary, interface science is excep-tional in its close, two-way interaction withtechnology. Only within the past few yearshave the tools and techniques become avail-able for a concerted attack on the scientificproblems of buried interfaces. Increased in-vestment is therefore both scientifically timelyand certain to pay significant dividends fortechnology.

2 4


Decision Making and Problem Solving

Research Briefing Panel onDecision Making and Problem Solving

Herbert A. Simon (Chairman), Carnegie-Mellon University, Pittsburgh, Pa.

George B. Dantzig, Stanford University,Stanford, Calif.

Robin Hogarth, University of Chicago,Chicago, Ill.

Charles R. Plott, California Institute ofTechnology, Pasadena, Calif.

Howard Raiffa, Harvard Business School,Boston, Mass.

Thomas C. Schelling, Harvard University,Cambridge, Mass.

Kenneth A. Shepsle, WashingtonUniversity, St. Louis, Mo.

Richard Thaler, Cornell University, Ithaca,N.Y.

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Amos Tversky, Stanford University,Stanford, Calif.

Sidney Winter, Yale Universi'v, NewHaven, Conn.

Staff

David A. Goslin, Executive Directur,Commission on Behavioral and SocialSciences and Education

Karan Ford, Administrative SecretaryAllan R. Hoffman, Executive Director,


26


Decision Making and Problem Solving

INTRODUCTION

The work of managers, of scientists, ofengineers, of lawyersthe work that steersthe course of society and its economic andgovernmental organizationsis largely workof making decisions and solving problems.It is work of choosing issues that requireattention, setting goals, finding or design-ing suitable courses of action, and evaluat-ing and choosing among alternative actions.The .first three of these activitiesfixingagendas, setting goals, and designing ac-tionsare usually called problem solving; thelast, evaluating and choosing, is usuallycalled decision making. Nothing is more im-portant for the well-being of society thanthat this work be performed effectively, thatwe address successfully the maT. --roblemsrequiring attention at the national level (thebudget and trade deficits, AIDS, nationalsecurity, the mitigation of earthquake dam-age), at the level of busine organizations(product improvement, efficiency of pro-duction, choice of investments), and at thelevel of our individual lives (choosing a ca-reer or a school, buying a house).

The abilities d skills that determine thequality of our decisions and problem solu-

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tions are stored not only in more than 200million human heads, but also in tools andmachines, and especially today in those ma-chines we call computers. This fund of brainsand its attendant machines form the basisof our American ingenuity, an ingenuity thathas permitted U.S. society to reach remark-able levels of economic productivity.

There are no more promising or impor-tant targets for basic scientific research thanunderstanding how human minds, with andwithout the help of computers, solve prob-lems and make decisions effectively, andimproving our problem-solving and deci-sion-n king capabilities. In psychology,economics, math,:matical statistics, opera-tions research, political science, artificial in-telligence, and cognitive science, majorresearch gains have been made during thepast half century in understanding problemsolving and decision making. The progressalready achieved holds forth the promise ofexciting new advances that will contributesubstantially to our nation's capacity fordealing intelligently with the range of is-sues, large and small, that confront us.

Much of our existing knowledge aboutdecision making and problem solving, de-rived from this research, has already been

2 7

put to use in a wide variety of applications,including procedures used to assess drugsafety, inventory control methods for in-dustry, the new expert systems that em-body ariificial intelligence techniques,procedures for modeling energy and envi-ronmental systems, and analyses of the sta-bilizing or destabilizing effects of alternativedefense strategies. (Application of the newinventory control techniques, for example,has enabled American corporations to re-duce their inventories by hundreds of mil-lions of dollars since World War II withoutincreasing the incidence of stockouts.) Someof the knowledge gained through the re-search describes the ways in which peopleactually go about making decisions andsolving problems; some of it prescribes bet-ter methods, offering advice for the im-provement of the process.

Central to the body of prescriptive knowl-edge about decision making has been thetheory of subjective expected utility (SEU),a sophisticated mathematical model of choicethat lies at the foundation of most contem-porary economics, theoretical statistics, andoperations research. SEU theory defines theconditions of perfect utility-maximizing ra-tionality in a world of certainty or in a worldin which the probability distributions of allrelevant variables can be provided by thedecision makers. (In spirit, it might be com-pared with a th -.1.17y of ideal gases or of fric-tionless bodies sliding down inclined planesin a vacuum.) SEU theory deals only withdecision making; it has nothing to say abouthow to frame problems, set goals, or de-velop new alternatives.

Prescriptive theories of choice such as SEUare complemented by empirical research thatshows how people actually make decisions(purchasing insurance, voting for politicalcandidates, or investing in securities), andresearch on the processes people use to solveproblems (designing switchgear or findingchemical reaction pathways). This researchdemonstrates that people solve problems byselective, heuristic search through large

problem spaces and large data bases, usingmeansends analysis as a principal tech-nique for guiding the search. The expert sys-tems that are now being produced byresearch on artificial intelligence and ap-plied to such tasks as interpreting oil-welldrilling logs or making medical diagnosesare outgrowths of these research findingson human problem solving.

What chiefly distinguishes the empiricalresearch on decision making and problemsolving from the prescriptive approachesderived from SEU theory is the attentionthat the former gives to the limits on humanrationality. These limits are imposed by thecomplexity of the world in which we live,the incompleteness and inadequacy of hu-man knowledge, the inconsistencies of in-dividual preference and belief, the conflictsof value among people and groups of peo-ple, and the inadequacy of the computa-tions we can carry out, even with the aid ofthe most powerful computers. The real worldof human decisions is not a world of idealgases, frictionless planes, or vacuums. Tobring it within the scope of human thinldngpowers, we nuisi simplify our problem for-mulations drastically, even leaving out muchor most of what is potentially relevant.

The descriptive theory of problem solvingand decision making is centrally concernedwith how people cut problems down to size:how they apply approximate, heuristic tech-niques to handle complexity that cannot behandled exactly. Out of this descriptivetheory is emerging an augmented andamended prescriptive theory, one that takesaccount of the gaps and elements of un-realism in SEU theory by encompassingproblem solving as well as choice and de-manding only the kinds of knowledge, con-sistency, and computational power that areattainable in the real world.

The growing realization that coping withcomplexity is central to human decisionmaking strongly influences thca directions ofresearch in this domain. Operations re-search and artificial intelligence are forging

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28

DECISION MAKING AND PROBLEM SOLVING

powerful new computational tools; at thesame time, a new body of mathematicaltheory is evolving around the topic of com-putational complexity. Economics, which hastraditionally derived both its descriptive andprescriptive approaches from SEU theory,is now paying a great deal of attention touncertainty and incomplete information; toso-called "agency theory," which takes ac-count of the institutional framework withinwhich decisions are made; and to gametheory, which seeks to deal with interindi-vidual and intergroup processes in whichthere is partial conflict of interest. Econo-mists and political scientists are also increas-ingly buttressing the empirical foundationsof their field by studying individual choicebehavior directly and by si?kiying behaviorin experimentally construcv::! markets andsimulated political structures.

The following pages contain a fuller out-line of current knowledge about decisionmaking and problem solving and a brief re-view of current research directions in thesefields as well as some of the principal re-search opportunities.

DECISION MAKING

SEU THEORY

The development of SEU theory was amajor intellectual achievement of the firsthalf of this century. It gave for the first timea formally axiomatized statement of what itwould mean for an agent to behave in aconsistent, rational manner. It assumed thata decision maker possessed a utility func-tion (an ordering by preference among allthe possible outcomes of choice), that all thealternatives among which choice could bemade were known, and that the conse-quences of choosing each alternative couldbe ascertained (or, in the version of the theorythat treats of choice under uncertainty, itassumed that a subjective or objective prob-ability distribution of consequences was as-sociated with each alternative). By admitting

21

subjectively assigned probabilities, SEUtheory opened the way to fusing subjectiveopinions with objective data, an approachthat can also be used in man-machine de-cision-making systems. In the probabilisticversion of the theory, Bayes's rule pre-scribes how people should take account ofnew information and how they should re-spond to incomplete information.

The assumptions of SEU theory are verystrong, permitting correspondingly stronginferences to be made from them. Althoughthe assumptions cannot be satisfied evenremotely for most complex situations in thereal world, they may be satisfied approxi-mately in some microcosmsproblem sit-uations that can be isolated from the world'scomplexity and dealt with independently.For example, the manager of a commercialcattle-feeding operation might isolate theproblem of finding the least expensive mixof feeds available in the market that wouldmeet all the nutritional requirements of hiscattle. The computational tool of linear pro-gramming, which is a powerful method formaximizing goal achievement or minimiz-ing costs while satisfying all kinds of sideconditions (in this case, the nutritional re-quirements), can provide the manager withan optimal feed mixoptimal within thelimits of approximation oi his model to real-world conditions. Linear programming andrelated operations research techniques arenow used widely to make decisions when-ever a situation that reasonably fits their as-sumptions can be carved out of its complexsurround. These techniques have been es-pecially valuable aids to middle manage-ment in dealing with relatively welhstructured decision problems.

Most of the tools of modern operationsresearchnot only linear programming, butalso integer programming, queuing theory,decision trees, and other widely used tech-niquesuse the assumptions of SEU theory.They assume that what is desired is to max-imize the achievement of some goal, underspecified constraints and assuming that all

2 9

alternatives and consequences (or theirprobability distributions) are known. Thesetools have proven their usefulness in a widevariety of applications.

THE LIMITS OF RATIONALITY

Operations research tools have also un-derscored dramatically the limits of SEUtheory in dealing with complexity. For ex-ample, present and prospective computersare not even powerful enough to provideexact solutions for the problems of optimalscheduling and routing of jobs through atypical factory that manufactures a varietyof products using many different tools andmachines. And the mere thought of usingthese computational techniques to deter-mine an optimal national policy for energyproduction or an optimal economic policyreveals their limits.

Computational complexity is not the onlyfactor that limits the literal application ofSEU theory. The theory also makes enor-inous demands on information. For the util-ity function, the range of availablealternatives and the consequences followingfrom each alternative must all be known.Increasingly, research is being directed atdecision making that takes realistic accountof the compromises and approximations thatmust be made in order to fit real-world prob-lems to the informational and computa-tional limits of people and computers, aswell as to the inconsistencies in their valuesand perceptions. The study of actual deci-sion processes (for example, the strategiesused by corporations to make their invest-ments) reveals massive and unavoidable de-partures from the framework of SEU theory.The sections that follow describe some ofthe things that have been learned aboutchoice under various conditions of incom-plete information, limited computing power,inconsistency, and institutional constraintson alternatives. Game theory, agency theory,choice under uncertainty, and the theory ofmarkets are a few of the directions of this

research, with the aims both of constructingprescriptive theories of broader application andof providing more realistic descriptions andexplanations of actual decision making withinU.S. economic and political institutions.

LIMITED RATIONALITY

IN ECONOMIC THEORY

Although the limits of human rationalitywere stressed by some researchers in the1950s, only recently has there been exten-sive activity in the field of economics aimedat developing theories that assume less thanfully rational choice on the part of businessfirm managers and other economic agents.The newer theoretical research undertakesto answer such questions as the following:

Are market equilibria altered by the de-partures of actual choice behavior from thebehavior of fully rational agents predictedby SEU theory?

Under what circumstances do the pro-cesses of competition "police" markets insuch a way as to cancel out the effects ofthe departures from full rationality?

In what ways are the choices made byboundedly rational agents different fromthose made by fully rational agents?

Theories of the firm that assume man-agers are aiming at "satisfactory" profits orthat their concern is to maintain the firm'sshare of market in the industry make quitedifferent predictions about economic equi-librium than those derived from the as-sumption of profit maximization. Moreover,the classical theory of the firm cannot ex-plain why economic activity is sometimesorganized around large business firms andsometimes around contractual networks ofindividuals or smaller organizations. Newtheories that take account of differential ac-cess of economic agents to information,combined with differences in self-interest,are able to account for these important phe-nomena, as well as provide explanations for

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3 0


the many forms of contracts that are usedin business. Incompleteness and asymme-try of information have been shown to beessential for explaining how individuals andbusiness firms decide when to lace uncer-tainty by insuring, when by hedging, andwhen by assuming the risk.

Most current work in this domain stillsumes that economic agents seek to rry:z.d-mize utility, but within limits posed by theincompleteness and uncertainty of the in-formOon available to them. An importantpotential area of research is to discover howchoices will be changed if there are otherdepartures from the axioms of rationalchoicefor example, substituting goals ofreaching specified aspiration levels (satis-ficing) for goals of maximizing.

Applying the new assumptions aboutchoice to economics leads to new empiri-cally supported theories about decisionmaking over time. The classical theory ofperfect rationality leaves no room for re-grets, second thoughts, or "weakness ofwill." It cannot explain why many individ-uals enroll in Christrnas savings plans, whichearn interest well below the market rate.More generally, it does not lead to correctconclusions about the important social is-sues of saving and conservation. The effectof pensions and social security on personalsaving has been a controversial issue in eco-nomics. The standard economic model pre-dicts that an increase in required pensionsaving will reduce other saving dollar fordollar; behavioral theories, on the other hand,predict a much smaller offset. The empiricalevidence indicates that the offset is indeedvery small. Another empirical finding is thatthe method of payment of wages and sal-aries affects the saving rate. For example,annual bonuses produce a higher saving ratethan the same amount of income paid inmonthly salaries. This finding implies thatsaving rates can be influenced by the waycompensation is framed.

If individuals fail to discount properly forthe passage of time, their decisions will not

23

be optimal. For example, air conditionersvary greatly in their energy efficiency; themore efficient models cost more initially butsave money over the long run through lowerenergy consumption. It has been found thatconsumers, on average, choose air condi-tioners that imply a discount rate of 25 per-cent or more per year, much higher thanthe rates of interest that prevailed at thetime of the study.

As recently as five years ago, the evidencewas thought to be unassailable that marketslike the New York St )ck Exchange work ef-ficientlythat prices eflect all available in-formation at any give, moment in time, sothat stock price movements resemble a ran-dom walk and contain no systematic infor-mation that could be exploited for profit.Recently, however, substantial departuresfrom the behavior predicted by the efficient-market hypothesis have been detected. Forexample, small firms appear to earn inexpli-cably high returns on the market prices oftheir stock, while firms that have very lowprice-earnings ratios and firms that havelost much of their market value in the recentpast also earn abnormally high returns. Allof these results are consistent with the em-pirical finding that decision makers oftenoverreact to new information, in violationof Bayes's rule. In the same way, it has beenfound that stock prices are excessively vol-atilethat they fluctuate up and down morerapidly and violently than they would if themarket were efficient.

There has also been a long-standing puz-zle as to why firms pay dividends. Consid-ering that dividends are taxed at a higherrate than capital gains, taxpaying investorsshould prefer, under the assumptions ofperfect rationality, that their firms reinvestearnings or repurchase shares instead ofpaying dividends. (The investors could sim-ply sell some of their appreciated shares toobtain the income they require.) The solu-tion to this puzzle also requires models ofinvestors that take account of limits on ra-tionality.

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THE THEORY OF GAMES

In economic, political, and other social sit-uations in which there is actual or potentialconflict of interest, especially if it is com-bined with incomplete information, SEUtheory faces special difficulties. In marketsin which there are many competitors (e.g.,the wheat market), each buyer or seller canaccept the market price as a "given" thatwill not be affected materially by the actionsof any single individual. Under these con-ditions, SEU theory makes unambiguouspredictions of behavior. However, when amarket has only a few supplierssay, forexample, twomatters are quite different.In this case, what it is rational to do dependson what one's competitor is going to do,and vice versa. Each supplier may try tooutwit the other. What then is the rationaldecision?

The most ambitious attempt to answerquestions of this kind was the theory ofgames, developed by von Neumann andMorgenstern and published in its full formin 1944. But the answers provided by thetheory of games are sometimes very puz-zling and ambiguous. In many situations,no single course of action dominates all theothers; instead, a whole set of possible so-lutions are all equally consistent with thepostulates of rationality.

One game that has been studied exten-sively, both theoretically and empirically, isthe Prisoner's Dilemma. In this game be-tween two players, each has a choice be-tween two actions, one trustful of the otherplayer, the other mistrustful or exploitative.If both players choose the trustful alterna-tive, both receive small rewards. If bothchoose the exploitative alternative, both arepunished. If one chooses the trustful alter-native and the other the exploitative alter-native, the former is punished much moreseverely than in the previous case, while thelatter receives a substantial reward. If theother player's choice is fixed but unknown,it is advantageous for a player to choose the

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exploitative alternative, for this will give himthe best outcome in either case. But if bothadopt this reasoning, they will both be pun-ished, whereas they could both receive re-wards if they agreed upon the trustful choice(and did not welch on the agreement).

The terms of the game have an unsettlingresemblance to certain situations in the re-lations between nations or between a com-pany and the employees' union. Theresemblance becomes stronger if one imag-ines the game as being played repeatedly.Analyses of "rational" behavior under as-sumptions of intended utility maximizationsupport the conclusion that the players will(ought to?) always make the mistrustfulchoice. Nevertheless, in laboratory experi-ments with the game, it is often found thatplayers (even those who are expert in gametheory) adopt a "tit-for-tat" strategy. Thatis, each plays the trustful, cooperative strat-egy as long as his or her partner does thesame. If the partner exploits the player ona particular trial, the player then plays theexploitative strategy on the next trial andcontinues to do so until the partner switchesback to the trustful strategy. Under theseconditions, the game frequently stabilizeswith the players pursuing the mutuallytrustful strategy and receiving the rewards.

With these empirical findings in hand,theorists have recently sought and foundsome of the conditions for attaining this kindof benign stability. It occurs, for example, ifthe players set aspirations for a satisfactoryreward rather than .seeking the maximumreward. This result 'is consistent with thefinding that in many situations, as in thePrisoner's Dilemma game, people appear tosatisfice rath:,r than attempting to optimize.

The Prisoner's Dilemma game illustratesan important point that is beginning to beappreciated by those who do research ondecision making. There are so many waysin which actual human behavior can departfrom the SEU assumptions that theoristsseeking to account for behavior are con-fronted with an embarrassment of riches.

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To choose among the many alternativemodels that could account for the anomaliesof choice, extensive empirical research iscalled forto see how people do make theirchoices, what beliefs guide them, what in-formation they have available, and what partof that information they take into accountand what part they ignore. In a world oflimited rationality, economics and the otherdecision sciences must closely examine theactual limits on rationality in order to makeaccurate predictions and to provide soundadvice on public policy.

EMPIRICAL STUDIES OF CHOICEUNDER UNCERTAINTY

During the past 10 years, empirical stud-ies of human choices in which uncertainty,inconsistency, and incomplete informationare present have produced a rich collectionof findings which only now are beginningto be organized under broad generaliza-tions. Here are a few examples. When peo-ple are given information about theprobabilities of certain events (e.g., howmany lawyers and how many engiwiers arein a population that is being sampled), andthen are given some additional informationas to which of the events has occurred (whichperson has been sampled from the popu-lation), they tend to ignore the prior prob-abilities in favor of incomplete or even quiteirrelevant information about the individualevent. Thus, if they are told that 70 percentof the population are lawyers, and if theyare then given a nonconunittal descriptionof a person (one that could equally well fita lawyer or an engineer), half the time theywill predict that the person is a lawyer andhalf the time that he is an engineereventhough the laws of probability dictate thatthe best forecast is always to predict that theperson is a lawyer.

People commonly misjudge probabilitiesin many other ways. Asked to estimate theprobability that 60 percent or more of the

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babies born in a hospital during a given weekare male, they ignore information about thetotal number of births, although it is evidentthat the probability oi a departure of thismagnitude from the expected value of 50percent is smaller if the total number of birthsis larger (the standard error of a percentagevaries inversely with the square root of thepopulation size).

There are situations in which people as-sess the frequency of a class by the ease withwhich instances can be brought to mind. Inone experiment, subjects heard a list of namesof persons of both sexes and were later askedto judge whether there were more names ofmen or women on the list. In lists presentedto some subjects, the men were more fa-mous than the women; in other lists, thewomen were more famous than the men.For all list., subjects judged that the sex thathad the more famous personalities was themore numerous.

The way in which an uncertain possibilityis presented may have a substantial effecton how people respond to it. When askedwhether they would choose surgery in a hy-pothetical medical emergency, many morepeople said that they would when the chanceof survival was given as 80 percent thanwhen the chance of death was given as 20percent.

On the basis of these studies, some of thegeneral heuristics, or rules of thumb, thatpeople use in making judgments have beencompiledheuristics that produce biasestoward classifying situations according totheir representativeness, or toward judgingfrequencies according to the availability ofexamples in memory, or toward interpre-tations warped by the way in which a prob-lem has been framed. These findings haveimportant implications for public policy. Arecent example is the lobbying effort of thecredit card industry to have differentials be-tween cash and credit prices labeled "cashdiscounts" rather than "credit surcharges."The research findings raise questions abouthow to phrase cigarette warning labels or

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frame truth-in-lending laws and informed-consent laws.

METHODS OF EMPIRICAL RESEARCH

Finding the underlying bases of humanchoice behavior is difficult. People cannotalways, or perhaps even usually, provideveridical accounts of how they make up theirminds, especially when there is uncertainty.In many cases, they can pedict how theywill behave (pre-election polls of voting in-tentions have been reasonably accurate whencarefully taken), but the reasons people givefor their choices can often be shown to berationalizations and not closely related totheir real motives.

Students of choice behavior have steadilyimproved their research methods. Theyquestion respondents about specific situa-tions, rather than asking for generaliza-tions. They are sensitive to the dependenceof answers on the exact forms of the ques-tions. They are aware that behavior in anexperimental situation may be different frombehavior in real life, and they attempt toprovide experimental settings an :. motiva-tions that are as realistic as possible. Usingthinking-aloud protocols and other ap-proaches, they try to track the choice be-havior step by step, instead of relying juston information about outcomes or queryingrespondents retrospectively about theirchoice processes.

Perhaps the most common method of em-pirical research in this field is still to askpeople to respond to a series of questions.But data obtained by this method are beingsupplemented by data obtained from care-fully designed laboratory experiments andfrom observations of actual choice behavior(for example, the behavior of customers insupermarkets). In an experimental study ofchoice, subjects may trade in an actual mar-ket with real (if modest) monetary rewardsand penalties. Research experience has alsodemonstrated the feasibility of making di-rect observations, over substantial pedods

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of time, of the decision-making processes inbusiness and governmental organizationsfor example, observations of the proceduresthat corporations use in making new in-vestments in plant and equipment. Confi-dence in the empirical findings that havebeen accumulating over the past several de-cades is enhanced by the general consis-tency that is observed among the dataobtained from quite different settings usingdifferent research methods.

There still remains the enormous andchallenging task of putting together thesefindings into an empirically founded theoryof decision making. With the growing avail-ability of data, the theory-building enter-prise is receiving much better guidance fromthe facts than it did in the past. As a result,we can expect it to become correspondinglymore effective in arriving at realistic modelsof behavior.

PROBLEM SOLVING

The theory of choice has its roots mainlyin economics, statistics, and operations re-search and only recently has received muchattention from psychologists; the theory ofproblem solving has a very different history.Problem solving was initially studied prin-cipally by psychologists, and more recentlyby researchers in artificial intelligence. It hasreceived rather scant attention from econ-omists.

CONTEMPORARYPROBLEM-SOLVING THEORY

Human problem solving is usually stud-ied in laboratory settings, using problemsthat can be solved in relatively short periodsof time (seldom more than an hour), andoften seeking a maximum density of dataabout the solution process by asking sub-jects to think aloud while they work. Thethinking-aloud technique, at first viewed withsuspicion by behaviorists as subjective and"introspective," has received such careful


methodological attention in recent years thatit can now be used dependably to obtaindata about subjects' behaviors in a wide rangeof settings.

The laboratory study of problem solvinghas been supplemented by field studies ofprofessionals solving real-world prob-lemsfor example, physicians making diag-noses and chess grandmasters analyzinggame positions, and, as noted earlier, evenbusiness corporations making investmentdecisions. Currently, historical records, in-cluding laboratory notebooks of scientists,are also being used to study problem-solv-ing processes in scientific discovery. Al-though such records are far less "dense"than laboratory protocols, they sometimespermit the course of discovery to be tracedin considerable detail. Laboratory note-books of scientists as distinguished as CharlesDarwin, Michael Faraday, Antoine-LaurentLavoisier, and Hans Krebs have been usedsuccessfully in such research.

From empirical studies, a description cannow be given of the problem-solving pro-cess that holds for a rather wide range ofactivities. First, problem solving generallyproceeds by selective search through largesets of possibilities, using rules of thumb(heuristics) to guide the search. Because thepossibilities in realistic problem situationsare generally multitudinous, trial-and-errorsearch would simply not work; the searchmust be highly selective. Chess grandmas-ters seldom examine more than a hundredof the vast number of possible scenarios thatconfront them, and similar small numbersof searches are observed in other kinds ofproblem-solving search.

One of the procedures often used to guidesearch is "hill climbing," using some mea-sure of approach to the goal to determinewhere it is most profitable to look next. An-other, and more powerful, common pro-cedure is meansends analysis. In meansends analysis, the problem solver comparesthe present squation with the goal, detectsa difference between them, and then searches

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memory for actions that are likely to reducethe difference. Thus, if the difference is a50-mile distance from the goal, the problemsolver will retrieve from memory knowl-edge about autos, carts, bicycles, and othermeans of transport; walking and flying willprobably be discarded as inappropriate forthat distance.

The third thing that has been learned aboutproblem solvingespecially when the sol-ver is an expertis that it relies on largeamounts of information that are stored inmemory and that are retrievable wheneverthe solver recognizes cues signaling its rel-evance. Thus, the expert knowledge of adiagnostician is evoked by the symptomspresented by the patient; this knowledgeleads to the recollection of what additionalinformation is needed to discriminate amongalternative diseases and, finally, to the di-agnosis.

In a few cases, it has been possible toestimate how many patterns an expert mustbe able to recognize in order to gain accessto the relevant knowledge stored in mem-ory. A chess master must be able to recog-nize about 50,000 different configurations ofchess pieces that occur frequently in thecourse of chess games. A medical diagnos-tician must be able to recognize tens of thou-sands of configurations of symptoms; abotanist or zoologist specializing in taxon-omy, tens or hundreds of thousands of fea-tures of specimens that define their species.For comparison, college graduates typicallyhave vocabularies in their native languagesof 50,000 to 200,000 words. (However, thesenumbers are very small in comparison withthe real-world situations the expert faces:there are perhaps 10120branches in the gametree of chess, a game played with only sixkinds of pieces on an 8 x 8 board.)

One of the accomplishments of the con-temporary theory of problem solving hasbeen to provide an explanation for the phe-nomena of intuition and judgment fre-quently seen in experts' behavior. The storea expert knowledge, "indexed" by the rec-

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ognition cues that make it accessible andcombined with some basic inferential ca-pabilities (perhaps in the form of meansends analysis), accounts for the ability ofexperts to find satisfactory solutions for dif-ficult problems, and sometimes to find themalmost instantaneously. The expert's "in-tuition" and "judgment" derive from thiscapability for rapid recognition linked to alarge store of knowledge. When immediateintuition fails to yield a problem solution orwhen a prospective solution needs to beevaluated, the expert falls back on the slowerprocesses of analysis and inference.

EXPERT SYSTEMS IN ARTIFICIAL INTELLIGENCE

Over the past 30 years, there has beenclose teamwork between research in psy-chology and research in computer scienceaimed at developing intelligent programs.Artificial intelligence (AI) research has bothborrowed from and contributed to researchon human problem solving. Today, artificialintelligence is beginning to produce sys-tems, applied to a variety of tasks, that cansolve difficult problems at the level ofprofessionally trained humans. These AIprograms are usually called expert systems.A description of a typical expert systemwould resemble closely the description givenabove of typical human problem solving; thedifferences between the two would be dif-ferences in degree, not in kind. An AI expertsystem, relying on the speed of computersand their ability to retain large bodies oftransient information in memory, will gen-erally use "brute force"sheer computa-tional speed and powermore freely thana human expert can. A human expert, incompensation, will generally have a richerset of heuristics to guide search and a largervocabulary of recognizable patterns. To theobserver, the computer's process will ap-pear the more systematic and even com-pulsive, the human's the more intuitive. Butthese are quantitative, not qualitative, dif-ferences.

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The number of tasks for which expert sys-tems have been built is increasing rapidly.One is medical diagnosis (two examples arethe CADUCEUS and MYCIN programs).Others are automatic design of electric mo-tors, generators, and transformers (whichpredates by a decade the invention of theterm "expert systems"), the configurationof computer systems from customer speci-fications, and the automatic generation ofreaction paths for the synthesis of organicmolecules. All of these (and others) are ei-ther being used currently in professional orindustrial practice or at least have reacheda level at which they can produce a profes-sionally acceptable product.

Expert systems are generally constructedin close consultation with the people whoare experts in the task domain. Using stan-dard techniques of observation and inter-rogation, the heuristics that the human expertuses, implicitly and often unconsciously, toperform the task are gradually educed, madeexplicit, and incorporated in program struc-tures. Although a great deal has been learnedabout how to do this, improving techniquesfor designing expert systems is an importantcurrent direction of research. It is especiallyimportant because expert systems, once built,cannot remain static but must be modifiableto incorporate new knowledge as it becomesavailable.

DEALING WITH ILL-STRUCTURED PROBLEMS

In the 1950s and 1960s, research on prob-lem solving focused on clearly structuredpuzzle-like problems that were easily broughtinto the psychological laboratory and thatwere within the range of computer pro-gramming sophistication at that time. Com-puter programs were written to discoverproofs for theorems in Euclidean geometryor to solve the puzzle of transporting mis-sionaries and cannibals across a river.Choosing chess moves was perhaps the mostcomplex task that received attention in theearly years of cognitive science and AI.

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As understanding grew of the methodsneeded to handle these relatively simpletasks, research aspirations rose. The nextmain target, in the 1960s and 1970s, was tofind methods for solving problems that in-volved large bodies of semantic informa-tion. Medical diagnosis and interpreting massspectrogram data are examples of the kindsof tasks that were investigated during this

L, od and for which a good level of un-cListanding was achieved. They are tasksthat, for all of the knowledge they call upon,are still well structured, with clear-cut goalsand constraints.

The current research target is to gain anunderstanding of problem-solving taskswhen the goals themselves are complex andsometimes ill defined, and when the verynature of the problem is successively trans-formed in the course of exploration. To theextent that a problem has these character-istics, it is usually called ill structured. Be-cause ambiguous goals and shifting problemformulations ate typical characteristics ofproblems of design, the work of architectsoffers a good example of what is involvedin solving ill-structured problems. An ar-chitect begins with some very general spec-ifications of what is wanted by a client. Theinitial goals are modified and substantiallyelaborated as the architect proceeds with thetask. Initial design ideas, recorded in draw-ings and diagrams, themselves suggest newcriteria, new possibilities, and new require-ments. Throughout the whole process of de-sign, the emerging conception providescontinual feedback that reminds the archi-tect of additional considerations that needto be taken into account.

With the current state of the art, it is justbeginning to be possible to construct pro-grams that simulate this kind of flexibleprablem-solving process. What is called foris an expert systen whose expertise in-cludes substantial knowledge about designcriteria as well as knowledge about the meansfor satisfying those criteria. Both kinds ofknowledge are evoked in the course of the

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design activity by the usual recognition pro-cesses, and the evocation of design criteriaand constraints continually modifies and re-molds the problem that the design systemis addressing. The large data bases that cannow be constructed to aid in the manage-ment of architectural and coistruction proj-ects provide a framework into which AI tools,fashioned along lines, can be incor-porated.

Most corporate strategy problems andgovernmental policy problems are at leastas ill structured as problems of architecturalor engineering design. The tools now beingforged for aiding architectural design willprovide a basis for building tools that canaid in formulating, assessing, and monitor-ing public energy or environmental policies,or in guiding corporate product and invest-ment strategies.

SETTING THE AGENDAAND REPRESENTING A PROBLEM

The very first steps in the problem-snlv-ing process are the least understood. Whatbrings (and should bring) problems to thehead of the agenda? And when a problemis identified, how can it be represented in away that facilitates its solution?

The task of setting an agenda is of utmostimportance because both individual humanbeings and human institutions have limitedcapacities for dealing with many tasks si-multaneously. While some problems are re-ceiving full attention, others are neglected.When new problems come thick and fast,"fire fighting" replaces planning and delib-eration. The facts of limited attention span,both for individuals and for institutions likethe Congress, are well known. However,relatively little has been accomplished to-ward analyzing or designing effectiveagenda-setting systems. A beginning couldbe made by the study of "alerting" orga-nizations like the Office of Technology As-sessment or military and foreign affairsintelligence agencies. Because the research

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and development function in industry is alsoin considerable part a task of monitoringcurrent and prospective technological ad-vances, it could also be studied profitablyfrom this standpoint.

The way in which problems are repre-sented has much to do with the quality ofthe solutions that are found. The task ofdesigning highways or dams takes on anentirely new aspect if human responses toa changed environment are taken into ac-count. (New transportation routes causepeople to move their homes, and peopleshow a considerable propensity to move intozones that are subject to flooding when par-tial protections are erected.) Very differentsocial welfare policies are usually proposedin response to the problem of providing in-centives for economic independence thanare proposed in response to the problem oftaking care of the needy. Early managementinformation systems were designed on theassumption that information was the scarceresource; today, because designers recog-nize that the scarce resource is managerialattention, a new framework produces quitedifferent designs.

The representation or "framing" of prob-lents is even less well understood thanagenda setting. Today's expert systems makeuse of problem representations that alreadyexist. But major advances in human knowl-edge frequently derive from new ways ofthinking about problems. A large part of thehistory of physics in nineteenth-century En-gland can be written in terms of the shiftfrom action-at-a-distance representations tothe field representations that were devel-oped by the applied mathematicians atCambridge.

Today, developments in computer-aideddesign (CAD) present new opportunities toprovide human designers with computer-generated representations of their prob-lems. Effective use of these capabilities re-quires us to understand better how peopleextract information from diagrams and otherdisplays and how displays can enhance hu-

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man performance in design tasks. Researchon representations is fundamental to theprogress of CAD.

COMPUTATION AS PROBLEM SOLVING

Nothing has been said so far about theradical changes that have been brought aboutin problem solving over most of the do-mains of science and engineering by thestandard uses of computers as computa-tional devices. Although a few examplescome to mind in which artificial intelligencehas contributed to these developments, theyhave mainly been brought about by researchin the individual sciences themselves, com-bined with work in numerical analysis.

Whatever their origins, the massive com-putational applications of computers arechanging the conduct of science in numer-ous ways. There are new specialties emerg-ing such as "computational physics" and"computational chemistry." Computa-tionthat is to say, problem solvingbe-comes an object of explicit concern toscientists, side by side with the substanceof the science itself. Out of this new aware-ness of the computational component of sci-entific inquiry is arising an increasinginteraction among computational specialistsin the various sciences and scientists con-cerned with cognition and AI. This inter-action extends well beyond the traditionalarea of numerical analysis, or even the newersubject of computational complexity, into theheart of the theory of problem solving.

Physicists seeking to handle the great massof bubble-chamber data produced by theirinstruments began, as early as the 1960s, tolook to AI for pattern recognition methodsas a basis for automating the analysis of theirdata. The construction of expert systems tointerpret mass spectrogram data and of othersystems to design synthesis paths for chem-ical reactions are other examples of problemsolving in science, as are programs to aid inmatching sequences of nucleic acids in DNA

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and RNA and amino acid sequences in pro-teins.

Theories of human problem solving andlearning are also beginning to attract newattention within the scientific community asa basis for improving science teaching. Eachadvance in the understanding of problemsolving and learning processes provides newinsights about the ways in which a learnermust store and index new knowledge andprocedures if they are to be useful for solv-ing problems. Research on these topics isalso generating new ideas about how effec-five learning takes placefor example, howstudents can learn by examining and ana-lyzing worked-out examples.

EXTENSIONS OF THEORY

Opportunities for advancing our under-standing of decision making and problemsolving are not limited to the topics dealtwith above, and in this section, just a fewindications of additional promising direc-tions for research are presented.

DECISION MAKING OVER TIME

The time dimension is especially trouble-some in decision making. Economics has longused the notion of time discounting and in-terest rates to compare present with futureconsequences of decisions, but as notedabove, research on actual decision makingshows that people frequently are inconsis-tent in their choices between present andfuture. Although time discounting is a pow-erful idea, it requires fixing appropriate dis-count rates for individual, and especiallysocial, decisions. Additional problems arisebecause human tastes and priorities changeover time. Classical SEU theory assumes afixed, consistent utility function, which doesnot easily accommodate changes in taste. Atthe other extreme, theories postulating alimited attention span do not have readyways of ensuring consistency of choice overtime.

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AGGREGATION

In applving our knowledge of decisionn'l ; .41,, lying to society-wide,0. on ori,..:11:Ation-wide, phenomena, theproblem of aggregation must be solved; thatis, ways must be found to extrapolate fromtheories of iodividual decision processes tothe net effccts on the whole economy, pol-ity, and society. Because of the wide varietyof ways in which any given decision taskcan be approached, it is unrealistic to pos-tulate a "representative firm" or an "eco-nomic man," and to simply lump togetherthe behaviors of large numbers of suppos-edly identical individuals. Solving the ag-gregation problem becomes more importantas more of the empirical research effort isdirected toward studying behavior at a de-tailed, microscopic level.

ORGANIZATIONS

Related to aggregation is the question ofhow decision making and problem solvingchange when attention turns from the be-havior of isolated individuals to the behav-ior of these same individuals operating asmembers of organizations or other groups.When people assume organizational posi-tions, they adapt their goals and values totheir responsibilities. Moreover, their deci-sions are influenced substantially by thepatterns of information flow and other com-munications among the various organiza-tion units,

Organizations sometimes display sophis-ticated capabilities far beyond the under-standing of single individuals. Theysometimes make enormous blunders or findthemselves incapable of acting. Organiza-tional performance is highly sensitive to thequality of the routines or "performance pro-grams" that govern behavior and to theadaptability of these routines in the face ofa changing environment. In particular, the"peripheral vision" of a complex organiza-tion is limited, so that responses to novelty

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in the environment may be made in inap-propriate and quasi-automatic ways thatcause major failure.

Theory development, formal modeling,laboratory experiments, and analysis of his-torical cases are all going forward in thisimportant area of inquiry. Although the de-cision-making processes of organizationshave been studied in the field on a limitedscale, a great many more such intensivestudies will be needed before the full rangeof techniques used by organizations to maketheir decisions is understood, and before thestrengths and weaknesses of these tech-niques are grasped.

LEARNING

Until quite recently, most research in cog-nitive science and artificial intelligence hadbeen aimed at understanding how intelli-gent systems perform their work. Only inthe past five years has attention begun toturn to the question of how systems becomeintelligenthow they learn. A number ofpromising hypotheses about learning mech-anisms are currently being explored. One isthe so-called connexionist hypothesis, whichpostulates networks that learn by changingthe strengths of their interconnections in re-sponse to feedback. Another learning mech-a nism that is being investigated is theadaptive production system, a computerprogram that learns by generating new in-structions that are simply annexed to theexisting program. Some success has beenachieved in constructing adaptive produc-tion systems that can learn to solve equa-tions in algebra and to do other tasks atcomparable levels of difficulty.

Learning is of particular importance forsuccessful adaptation to an environment thatis changing rapidly. Because that is exactlythe environment of the 1980s, the trend to-ward broadening research on decision mak-ing to include learning and adaptation iswelcome.

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This section has by no means exhaustedthe areas in which exciting and importantresearch can be launched to deepen under-standing of decision making and problemsolving. But perhaps the examples that havebeen provided are sufficient to convey thepromise and significance of this field of in-quiry today.

CURRENT RESEARCH PROGRAMS

Most of the current research on decisionmaking and problem solving is carried onin universities, frequently with the supportof government funding agencies and pri-vate foundations. Some research is done byconsulting firms in connection with their de-velopment and application of the tools ofoperations research, artificial intelligence,and systems modeling. In some cases, gov-ernment agencies and corporations havesupported the development of planningmodels to aid them in their policy plan-ningfor example, corporate strategicplanning for investments and markets andgovernment planning of environmental andenergy policies. There is an increasing num-ber of cases in which research scientists aredevoting substantial attention to improvingthe problem-solving and decision-makingtools in their disciplines, as we noted in theexamples of automation of the processingof bubble-chamber tracks and of the inter-pretafion of mass spectrogram data.

To use a generous estimate, support forbasic research in the areas described in thisdocument is probably at the level of tens ofmillions of dollars per year, and almost cer-tainly, it is not as much as $100 million. Theprindpal costs are for research personneland computing equipment, the former beingconsiderably larger.

Because of the interdisciplinary characterof the research domain, federal researchsupport comes from a number of differentagencies, and it is not easy to assess the totalpicture. Within the National Science Foun-dation (NSF), the grants of the decision and

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management sciences, politic science andthe economics programs in the Social Sci-ences Division are to a considerable extentdevoted to projects in this domain. Smalleramounts of support come from the memoryand cognitive processes program in the Di-vision of Behavioral and Neural Sciences,and perhaps from other programs. The"software" component of the new NSF Di-rectorate of Computer Science and Engi-neering contains programs that have alsoprovided important support to the study ofdecision making and problem solving.

The Office of Naval Research has, overthe years, supported a wide range of studiesof decision making, including important earlysupport for operations research. The mainsource of funding for rese..ch in AI has beenthe Defense Advanced Research ProjectsAgency (DARPA) in the Department of De-fense; important support for research on ap-plications of AI to medicine has beenprovided by the National Institutes of Health.

Relevant economics research is also fundedby other federal agencies,including theTreasury Department, the Bureau of LaborStatistics, and the Federal Reserve Board. Inrecent years, basic studies of decision mak-ing have received only relatively minor sup-port from these sources, but because of therelevance of the research to their missions,they could become major sponsors.

Although a number of projects have beenand are funded by private foundations, thereappears to be at present no foundation forwhich decision making and problem solvingare a major focus of interest.

In sum, the pattern of support for re-search in this field shows a healthy diversitybut no agency with a clear lead responsi-bility, unless it be the rather modestly fundedprogram in decision and management sci-ences at NSF. Perhaps the largest scale ofsupport has been provided by DARPA,where decision making and problem solv-ing are only components within the largerarea of artificial intelligence and certainlynot highly visible research targets.

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The character of the funding require-ments in this domain is much the same asin other fields of research. A rather intensiveuse of computational facilities is typical ofmost, but not all, of the research. And be-cause the field is gaining new recognitionand growing rapidly, there are special needsfor the support of graduate students andpostdoctoral training. In the computing-in-tensive part of the domain, desirable re-search funding per principal investigatormight average $250,000 per year; in empir-ical research involving field studies and large-scale experiments, a similar amount; and inother areas of theory and laboratory exper-imentation, somewhat less.

RESEARCH OPPORTUNITIES:SUMMARY

The study of decision making and prob-lem solving has attracted much attentionthrough most of this century. By the end ofWorld War II, a powerful prescriptive theoryof rationality, the theory of subjective ex-pected utility (SEU), had taken form; it wasfollowed by the theory of games. The past40 years have seen widespread applicationsof these theories in economics, operationsresearch, and statistics, and, through thesedisciplines, to decision making in businessand government.

The main limitations of SEU theory andthe developments based on it are its relativeneglect of the limits of human (and com-puter) problem-solving capabilities in the faceof real-world complexity. Recognition ofthese limitations has produced an increas-ing volume of empirical research aimed atdiscovering how humans cope with com-plexity and reconcile it with their boundedcomputational powers. Recognition that hu-man rationality is limited occasions no sur-prise. What is surprising are some of theforms these limits take and the kinds of de-partures from the behavior predicted by theSEU model that have been observed. Ex-tending empirical knowledge of actual hu-

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man cognitive processes and of techniques fordealing with complexity continues to be a re-search goal of very high priority. Such em-pirical knowledge is needed both to build validtheories of how the U.S. society and economyoperate ar to build prescriptive tools for de-cision n. ,; that are compatible with exist-ing ann4 -.1.!: donal capabilities.

The co:r.plementary fields of cognitivepsychology and artificial intelligence haveproduced in the past 30 years a fairly well-developed theory of problem solving thatlends itself well to computer simulation, bothfor purposes of testing its empirical validityand for augmenting human problem-solv-ing capacities by the construction of expertsystems. Problem-solving research today isbeing extended into the domain of ill-struc-tured problems and applied to the task offormulating problem representations. Theprocesses for setting the problem agenda,which are still very little explored, deservemore research attention.

The growing importance of computa-tional techniques in all of the sciences hasRttracteri new attention to numerical anal-ysis and to the topic of computational com-plexity. The need to use heuristic as well asrigorous methods for analyzing very com-plex domains is beginning to bring about awide interest, in various sciences, in thepossible application of problem-solving the-ories to computation.

Opportunities abound for productive re-search in decision making and problemsolving. A few of the directions of researchthat look r.'specially promising and signifi-cant follow:

A substantially enlarged program ofempirical studies, involving direct obser-vation of behavior at the level of the indi-vidual and the organization, and includingboth laboratory and field experiments, willbe essential in sifting the wheat from thechaff in the large body of theory that nowexists and in giving direction to the devel-opment of new theory.

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Expanded research on expert systemswill require extensive empirical study of ex-pert behavior and will provide a setting forbasic research on how ill-structured prob-lems are, and can be, solved.

Decision making in organizational set-tings, which is much less well understoodthan individual decision making and prob-lem solving, can be studied with great profitusing already established methods of in-quiry, especially through intensive long-range studies within individual organiza-tions.

The resolution of conflicts of values (in-dividual and group) and of inconsistenciesin belief will continue to be highly produc-tive directions of inquiry, addressed to is-sues of great importance to society.

Setting agendas and framing problemsare two related but poorly understood pro-cesses that require special research attentionand that now seem open to attack.

These five areas are examples of especiallypromising research opportunities drawn fromthe much larger set that are described orhinted at in this report.

The tools for decision making developedby previous research have already found ex-tensive application in business and govern-ment organizations. A number of suchapplications have been mentioned in thisreport, but tl-ey so pervade organizations,especially at the middle management andprofessional levels, that people are often un-aware of their origins.

Although the research domain of decisionmaking and problem solving is alive andwell today, the resources devoted to thatresearch are modest in scale (of the order oftens of millions rather than hundreds of mil-lions of dollars). They are not commensur-ate with either the identified researchopportunities or the human resources avail-able for exploiting them. The prospect ofthrowing new light on the ancient problemof mind and the prospect of enhancing thepowers of mind with new computational


tools are attracting substantial numbers offirst-rate young scientists. Research prog-ress is not limited either by lack of excellentresearch problems or by lack of human tal-ent eager to get on with the job.

Gaining a better understanding of howproblems can be solved and decisions madeis essential to our national goal of increasingproductivity. The first industrial revolutionshowed us how to do most of the world'sheavy work with the energy of machines

35

instead of human muscle. The new indus-trial revolution is showing us how much ofthe work of human thinking can be done byand in cooperation with intelligent ma-chines. Human minds with computers toaid them are our principal productive re-source. Understanding how that resourceoperates is the main road open to us forbecoming a more productive society and asociety able to deal with the many complexproblems in the world today.

43


Protein Structure and Biological Function

Research Briefing Panel onProtein Structure and Biological Function

Frederic Richards (Chairman), YaleUniversity, New Haven, Conn.

Robert Baldwin, Stanford UniversityMedical Center, Palo Alto,, Calif.

Gerald R. Galluppi, Monsanto Company,St. Louis, Mo.

Robert Griffin, Massachusetts Institute ofTechnology, Cambridge, Mass.

Emil Thomas Kaiser, RockefellerUniversity, New York, N.Y.

Brian Matthews, University of Oregon,Eugene, Oreg.

J. Andrew McCammon, University ofHouston-University Park, Houston, Tex.

Alfred Redfield, Brandeis University,Waltham, Mass.

Brian Reid, University of Washington,Seattle, Wash.

Robert Sauer, Massachusetts Institute ofTechnology, Cambridge, Mass.

Alan Schechter, National Institutes ofHealth, Bethesda, Md.

Paul Sigler, University of Chicago,Chicago, Ill.

Peter von Hippel, University of Oregon,Eugene, Oreg.

Don Wiley, Harvard University,Cambridge, Mass.

Staff

Barbara Filner, Director, Division of HealthSciences Policy, Institute of Medicine

Naomi Hudson, Administrative SecretaryAllan R. Hoffman, Executive Director,


38

45


Protein Structure and Biological Function

INTRODUCTION

Proteins are involved in every biologicalfunction. As enzymes, they catalyze thechemical reactions of cells. As hormores andgrowth factors, they regulate the develop-ment of cells and coordinate the functionsof distant organs in the body. In variousfilamentous forms, they control the shapeof cells and the dramatic alterations that oc-cur during cell division. In muscle, proteinschange chemical energy into mechanical en-ergy and cause movement. As component.;of membranes, they control the traffic ofmolecules and information among the var-ious cellular compartments. Hemoglobin, aprotein in blood, is specifically designed totransport oxygen between organs; otherblood proteins, such as clotting factors andcirculating antibodies, act as defenses againsttrauma and infectiurk. In plants, a highlyorganized collection of membrane proteinsis involved in the complex process of pho-tosynthesis, without which there would beno higher animal forms.

Proteins are polymer molecules com-posed of amino acids that are connected bylinks known as peptide bonds. An individ-ual protein molecule may contain hundreds

39

or thousands of amino acids arranged in one,or several, polypeptide chains. Each chainfolds into a particular three-dimensionalconfiguration that is essential for its highlyspecific biological function. In this report,we focus on the experimental and theoret-ical investigation of the three-dimensionalstructure of proteins, at the level of reso-lution of individual atoms.

The study of protein structures, fre-quently referred to as structural biology, isin a period of great excitement brought aboutby developments in several fields. Manyproteins of special interest are now availablein unprecedented amounts. The chemicalsynthesis of polypeptide chains of increas-ing size has steadily improved over the past20 years, and recently a chain length of over100 amino acids was achieved. In the past5 years, the biological synthesis of proteins,through cloning, has been reduced to stan-dard practice, not only in the laboratory butalso on a commercial scale. These comple-mentary procedures supply proteins of de-fined sequence in substantial amounts. Atthe same time, spectacular advances havebeen made in x-ray diffraction and nuclearmagnetic resonance spectroscopy, two tech-niques for determining structure. New pro-

46

cedures and refined equipment have ex-panded the range of application and the sizeof the proteins that can be studied. Chem-ical theory also has been developing at arapid rate, especially those branches relatedto polymers. Furthermore, with the distri-bution of faster, smaller, and less expensivecomputer hardware, there has been con-stant improvement in access to more ad-vanced computing capability, a factor thathas played an important role in theoreticaland experimental studies. The coming to-gether of these separate developments makesstructural biology ready for an explosive in-crease in the determination and under-standing of high-resolution structures ofproteins and protein complexes.

The new surge of structural informationwill dramatically improve our understand-ing of the processes of biological control andwill guide the design of proteins or otherproducts that will be developed either tocause purposeful malfunctions (e.g., insec-ticides) or to correct natural malfunctions(e.g., to improve human health). Guided bythe three-dimensional structure, changes canbe introduced into the sequence of an en-zyme that can alter the specificity of the cat-alyzed reaction and/or its catalytic rate. Inaddition, structural analysis may reveal sp-cific differences in essential enzymes thacwill enable geneticists to engineer proteinsequences, or drug designers to produce re-agents, that will selectively counter harmfulbacteria or insects without harming the host.

RESEARCH GOALS

THE FOLDING PROBLEM

Inside a cell, amino acids are assembledinto peptide chains by a complex systemthat translates the genetic message into spe-cific amino acid sequences. Following syn-thesis, the chains fold into compact proteinmolecules. For many isolated polypeptides,conditions can be provided in which thisfolding step will occur spontaneously,

40

yielding a biologically active molecule iden-tical to the native, cell-derived protein. Thus,all of the information required to producethe final structure is contained in the aminoacid sequence. The prediction of the de-tailed three-dimensional structure of a pro-tein from a given sequence is known as thefolding problem. It is the most fundamentalproblem at the chemistrybiology interface,and its solution has the highest long-rangepriority.

The folding problem is not only a majorintellectual challenge but also an urgent andimmediate problem at the practical level inbiotechnology. Successful industrial pro-duction of a biologically active protein fre-quently depends on the ability to induce acloned polypeptide to fold correctly.

PROTEIN STABILITY

Protein stability is a specific issue withinthe folding problem. Thermodynamically,protein structures are only marginally sta-ble, and small changes can substantially in-crease or decrease their effective stability.Not only is prediction of stability a strin-gent, but elusive, test of theoretical un-derstanding, but also direct practical appli-cations, through genetic engineering of pro-teins, are immediately at hand. Resistanceto thermal destruction or to degradation byenzymes secreted by microorganisms, forexample, are highly desirable properties forpharmacological agents and enzymes in in-dustrial use.

LIGAND BINDING

The specificity and strength with whichligands, either small or large molecules, bindto proteins is a central feature of biologicalfunction. The result of this binding may besimple sequestration for storage or removal,a catalytic event if the protein is an enzyme,the development and transmission of a sig-nal if the protein is a receptor, or the switch-ing off of a gene if it is a repressor. The

4 7

PROTEIN STRUCTURE AND BIOLOGICAL FUNCTION

ability to predict the structure either of aprotein ligand or an active sitethe part ofthe plotein where the ligand bindsis cen-tral to the rational design of new drugs ornew enzymes.

SIGNAL TRANSMISSION

Signal transmission from one part of amolecule to another is essential for the reg-ulation of complex enzymes and for the ac-tivity of many receptor systems. Itsmechanism, however, is poorly under-stood. Changes in the dynamic propertiesof an entire protein molecule can be causedby the binding of a ligand to a relativelysmall active site; this phenomenon has clearimplications for information transfer. In someproteins, however, similar interactions pro-duce or)14/ localized changes in structure ordynamic:- Fuli understanding will only comethrough a d&ailed study of the relevantstructures and their properties.

RECENT ADVANCES IN KNOWLEDGE

About 300 protein structures are known,and about 10 to 20 new structures are re-ported each year. In many cases, knowledgeof these structures has brought us closer tothe goals outlined aboveunderstandingfolding, stability, ligand binding, signaltransmission, and catalytic activity. A fewexamples will illustrate what has beengleaned from studies of structure and thepotential applications of the knowledge.

Angiotensin is a chemical in human bloodthat is involved in regulation of blood pres-sure. When it is modified by an enzymeknown as angiotensin-converting enzyme(ACE), it causes a rapid increase in bloodpressure. Control of high blood pressureseemed possible if an inhibitor of ACE couldbe found. At the time a drug developmentprogram was started, ACE had not been iso-lated in pure form from humans. But thestructure of an enzyme from the pancreasof cows, which happens to catalyze a chem-

41

ically similar reaction, was known at highresolution. Based on the detailed structureof the animal enzyme, especially the cata-lytic binding site, it was possible to make amodel for the active site of human ACE.With this model, the drug captopril, a stronginhibitor of human ACE, was successfullydesigned and synthesized. Subsequently,protein chemistry was used to design ena-lapril, a new drug in which some of theunwanted side effects of captopril have beeneliminated.

Influenza virus offers another example.This virus causes recurring epidemics (andthe continuing need for development of newvaccines) because its surface proteins varyso much. Recently, the structure of hae-magglutinin, a surface protein, was deter-mined. Consequently, the regions that varywith the strain of virus have been located.Even more promising is the discovery of aregion that does not vary; it provides a pocketin the protein and rimy be an excellent targetfor drug development. The full high-reso-lution structure was essential to the discov-ery of this region. Recent structural studiesof the cold and polio viruses and adenovi-ruses have opened up similar exciting op-portunities.

The recent determination of the structureof a part of an enzyme called DNA poly-merase I, in conjunction with related kineticstudies, is beginning to lay a general foun-dation for understanding how "processive"enzyme reactions work. Such enzymes latchonto a long molecule (the DNA thread inthe case of DNA polymerase) and then moverapidly along it without letting go, muchlike a train on a track. Such a mechanism isentirely new in the field of enzymology. Notonly is this fascinating to biochemists study-ing the replication of DNA and RNAofcentral importance to lifebut the practicalimportance is considerable. The processivedigestion of polysaccharides and othermacromolecules is of great importance tofood processing and pharmaceutical indus-tries, for example.

4 8

Instrumentation developments have beenessential to these and numerous other ex-amples of major progress in structural bi-ology. New or improved instrumentation hasled to tremendous savings of time and man-power, as well as to unique routes for solv-ing research problems. Accordingly, muchof the remainder of this report will focus onresearch advances in instrumentation anddata analysis.

TECHNOLOGICAL ADVANCES

X-RAY DIFFRACTION

Since the early 1960s, x-ray crystallogra-phy has continued to provide us with themost detailed and comprehensive picture ofthree-dimensional protein structure. Whenx-rays are passed through a crystal, they arediffracted in many directions, and the ge-ometry and intensity of the many diffractedbeams ar :.3. directly related to the structureof the crystal. Improvements in x-ray sources,in data collection equipment, and in thepower and availability of computers are ex-pected to continue to enhance the power ofthese structure studies.

Area Detectors

The diffraction pattern from a crystal canbe recorded all at once (with a photographicfilm) or one beam at a time (with an appro-priate counter). Data on film must be readoptically and then must be converted to adigital form to determine the intens;ty ofeach beam. Area detectors are a major newinnovation in such data collection. They havethe advantage of direct counting while re-taining the multiple recording capability offilmwith a higher signal-to-noise ratio.Analyses that took weeks or months havebeen reduced to hours, with a considerablegain in accuracy.

This time-saving device has had far-reaching effects on the kinds of experimentsthit are being planned. For example, it will

42

now be possible to take full advantage ofthe ability of molecular genetics to generatemany different mutational changes in a sin-gle protein. The crystallographic examina-tion of the different forms of a given proteinwill be practical for a small group of inves-tigators, or even a single individual. Thecomparison of structures will be of inesti-mable value in elucidating determinants ofstructure and structure/function relation-ships.

Synchrotron X-Ray Sources

Synchrotron x-ray sources are becomingavailable at various national facilities, andtheir accessibility provides unique oppor-tunities. Because synchrotron radiation hasa continuously varying wavelength, it ispossible to collect data at two or more dif-ferent wavelengths. Proper combination ofthe data sets provides substantial help inovercoming the major stumbling block insolving an unknown structure.

The high intensity of the synchrotron ra-diation also far exceeds that of any usuallaboratory source. It is possible to collectenough data for structure definition in 10 to100 milliseconds, and perhaps even fasterin the future. With such high data rates, fullstructural studies of short-lived intermedi-ates in enzyme reactions are possible inprinciple. The determination of the struc-ture of such intermediates at physiologicaltemperatures would lead to a dramatic im-provement of our understanding of enzymecataiysis. Currently, intermediate states canonly be studied when stabilized under un-usual conditions, such as very low temper-ature, so there is always uncertainty aboutthe relevance of any findings to the actualcatalytic process.

The full benefits of fast synchrotron datacollection are not yet being realized becausethe diffracted intensities are recorded onphotographic film. More effective use ofsynchrotron facilities for protein structureinvestigations will require a high-flux area de-

4 9


tector capable of recording perhaps 108 eventsper second. This is at least 1,000 times fasterthan the commercial instruments now avail-able for laboratory use.

Computing and Graphics

X-ray studies require computers for dataanalysis and interpretation. Model refine-ment to get the "best" structure is particu-larly computer-intensive. Computer-aidedmolecular graphics plays an increasing rolein the solution of structure and in subse-quent study of the structure. Color is rou-tine and is now central to the effective useof graphics as a laboratory tool. It is possibleto examine very complex structureE: :And toselectively "flag" special features or prop-erties by color-coding the atoms. Spatial re-lations that would be extremely difficult todetect by computation become very obviousto the human eye. The emphasis on graph-ics is likely to continue, even with markedimprovements Li automatic data analysis,which is itself highly computer-intensive.

Neutron Diffraction

Neutron diffraction hag a special role instructure studies because of i unique abil-ity to reveal the position of hydrogen atoms.These atoms are frequently of central im-portance in enzyme-catalyzed reactions, butbecause hydrogen is so light, it is poorlydetectedif at allin x-ray structures ofproteins. However, hydrogen is easily "seen"by neutrons, although such experiments canonly be carried out at the national laboratoryreactors. Together with the hoped-for up-grading of the high-flux reactors, the de-velopment and capabilities of the new pulseneutron source at Los Alamos will be watchedwith great interest.

Crystallization

Protein, crystals are unusual examples ofthe solid state in that they contain a large

43

amount of liquid water. The structure of thoseproteins for which comparisons have beenmade is essentially identical in a crystal andin aqueous solution.

Production of the highly ordered crystalsrequired for x-ray diffraction studies re-mains an art rather than a science. None-theless, the number of crystallized proteinsis increasing rapidly. Of special note is therecent successful crystallization of integralmembrane proteins such as the photosyn-thetic reaction center and bacterial rhodop-sin.

NUCLEAR MAGNETIC RESONANCE

With a nuclear magnetic resonance (NMR)spectrum, researchers measure the absorp-tion of radio-frequency energy by the nucleiof molecules placed in a magnetic field. Thefrequency at which an atomic nucleus ab-sorbs radiation is very sensitive to the chem-ical environment provided by the structureof the molecule. A basic problem, however,has been the identification of whkh peak inthe spectrum belongs to which atomic nu-cleus in the structure. New data collectiontechniques have been developed to extractinformation about the distances betweenneighboring atoms, and these techniqueshave revolutionized the study of proteinsup to approximately 12,000 in molecularweight. From these identified spectra, sci-entists can derive characteristic patterns ofsubstructures in the protein. More detailedanalysis with computer-intensive distancegeometry algorithms can provide the fullthree-dimensional structure in favorablecases.

The recent progress in research on smallproteins has been directed toward the de-termination of average structures in solutionfor comparison with models from x-ray dif-fraction. This work has set the stage for thenext fascinating phase of NMR, the strHyof changes in structure that are induced, ...)1example, by the binding of ligands. Whilemuch of this work will be done in partner-

ship with investigators using x-ray diffrac-tion, many problems are only accessiblethrough NMR proceduresnotably thosecases in which crystalline materids cannotbe obtained. Unique opportunities exist tolearn about partially or totally disorderedmolecules that are important both in equi-librium populations and as reaction inter-mediates.

Defining procedures for the precise ma-nipulation of nuclear spin in a moleculespin engineeringwill continue to play animportant role in the development of op-erating procedures for NMR spectrometers,especially for macromolecules with theircomplex spin systems. An appropriate se-quence of radio-frequency pulses can dras-tically simplify a complex spectrum, revealrelations between spatially distant atoms,and greatly assist in the essential step ofassigning peak signals to portions of theprotein structure. Further developments re-quire that young investigators with a back-ground in quantum physics be attracted tothis particular area of structural biology.

Several other techniques designed forstructures larger than those with molecularweights of 15,000 to 20,000 have also beendeveloped. Solid-state NMR .has no inher-ent size limit, and there are very interestingapplications for membrane proteins or fi-brous materials, such as collagen, which areintrinsically insoluble. Another approach isthe direct study of small substrates or in-hibitors interacting with active sites of largeenzymes. A number of new developmentsare being intensively pursued in this area,such as the use of labeled, tightly boundsubstrates. A third approach is to simplifythe spectra by preparing samples with sta-ble isotopes inserted in a limited number ofknown positions. By a combination ofchemical and biological procedures, aminoacids are prepared with the isotopes 2H, 13C,or 15N in appropriate positions. These areincorporated into proteins at known loca-tions. The syntheses are often difficult, butthe rewards are great because the spectra of

44

the isotopically substituted proteins can bevery simple and easy to interpret. More-over, this technique can produce very largesignals in comparison with the low back-ground absorption. Even low concentra-tions of relatively unstable intermediates,such as are likely to be important in theprotein folding problem, may be detectablein these enriched samples. And as a furtherbenefit, data collection times are markedlyshortened.

SYNTHESIS OF PROTEINS

Sensitivity and sample size continue tolimit both x-ray crystallography and NMR,which require amounts of material in the 10-to 100-mg range. An adequate quantity ofhighly purified proteins of specified se-quence, and, where required, with specificisotopic substitutions, is essential to bio-physical study of structure and function.Within different "out overlapping size ranges,quantities of p. teins can be produced to-day either by cl. 11 or biological proce-dures.

Chemical Synthesis

Solid-phase chemical synthesis has beeneffectively automated, and peptides 30 to 40amino acids long are readily produced ingood yield. Substant_ally longer peptides alsohave been synthesized, and continuing im-provement can be expected. The next steptoward the synthesis of longer chains is thecondensation of preformed fragments. Con-densation is possible by enzymatic as weilas chemical methods, but general proce-dures are not as well worked out and de-serve considerably more study.

Chemical synthesis allows the insertionof an isotopically labeled amino acid, anamino acid derivative, or even a nonnaturalamino acid in any single position in the chain.Multiple-site "mutations" at any selectedgroup of sites thus become easy to produce.In the synthesis of drugs that mimic pep-


tides, even the peptide bond may be cir-cumvented in specified locations, leading toresistance to degradation.

Limitations in chemical synthesis at thistime derive from the problem of optical pu-rity, the yield of the correct sequence, andthe roughly linear relationship between theamount of the product and the cost of pro-ducing it. However, these limitations, as wellas the limitation on chain length, are over-come in some biotechnology processes.

Biological Synthesis

The procedures that are used to produceproteins in high yield by cloning in bacteriaare well developed. The companion proce-dures for producing single amino acidchanges by site-directed mutagenesis aresimple, fast, and reliable. In many cases, thefusion of a special "signal sequence" to theprotein will result in its secretion, which as-sists in proper folding. Nonetheless, clon-ing is not always successful. Degradation ofthe product can severely reduce the yield;inside the bacterial cell, the chain may notfold to yield the desired, biologically activemolecule; and modification of certain aminoacids after polymerization of the protein asrequired for various eukaryotic proteins("post-translational" modification) does notoccur in bacteria.

Cloning in eukaryotic systems, particu-larly human cell culture, is not yet as welldeveloped and is very expensive for pro-ducing proteins in commercial quantities.Improved expression vectors to overpro-duce the desired protein, protease-deficientstrains, rapid lysis methods, and better bio-chemical separation procedures are all re-quired. Two important research opportunitiesare development of better methods for multiplesite-directed changes at positions widely sepa-rated in the sequence, and the development ofhigh expression systems for eukaryotic proteins.

It is equally important that these new pro-tein products be characterized rapidly Pre-liminary structure evaluations by standard

45

biophysical procedures, particularly the var-ious forms of optical spectroscopy, enablescreening of protein products and selectionof the most interesting for detailed study byx-ray and NMR techniques.

THEORY

Theoretical studies of proteins are onlybeginning to have a real impact in relationto biological function. The field has beenstimulated by advances in computer tech-nology, theoretical chemistry, and experi-mental biochemistry. It is clear that the.oreticalstudies will play a major role in the designof new proteins and of molecules with whichproteins interact.

The most highly developed theoreticalmethods involve molecular dynamics sim-ulations, in which computers are used tosimulate atomic motions in a protein and itssurroundings. When combined with a newapproach giving thermodynamic parame-ters for reactions, dynamic simulations canbe used to make predictions concerning rec-ognition and binding among proteins andother molecules. This method has recentlybeen used successfully to calculate the af-finity in an enzyme-inhibitor interaction; ithas promise for studies of protein folding,stability, covalent reactivity, and noncova-lent association. Practical applications in-clude the design of thugs, enzymes,antibodies, and other molecules.

The rates and mechanisms of enzyme-cat-alyzed reactions and lisand binding are po-tentially accessible through moleculardynamics. A modification known as Brown-ian dynamics is useful for extending calcu-lations into the time range of somewhatslower biological processes. A number ofother theoretical approaches, clearly on thehorizon, may be useful for predicting thestructures of short peptides in solution.

Continuing attention should be directedto improving the basic mathematical func-tions and input parameters that are neededboth in molecular dynamics and energy

52

minimization procedures; to improving thetreatment of electrostatic interactions; andto the detailed treatment of the waterpro-tein interface where biological activity is ex-pressed. More ad hoc approaches in applyingother aspects of basic chemical theory mayalso be useful in attacking the protein fold-ing problem in which the proper applicationof first principles is still elusive.

BOTTLENECKS ANDRECOMMENDATIONS

Progress in solving the scientific problemsof structural biology will require both per-sonnel qualified in this multidisciplinary areaand sophisticated equipment in individuallaboratories and national centers. For struc-tural biology to achieve its full potential incontributing to fundamental science, med-icine, agriculture, and the chemical indus-tries, a number of policy concerns shouldbe addressel.

1. Basic Research Support Of absolutelycentral concern in this area. as in others, ismaintenance of support for basic research pro-grams at the level of the individual investi-gator and small consortia.

2. Professional Personnel Of comparableconcern is the continuing supply and trainingof professional personnel. Scientific opportun-ities will not be realized, and the equipmentinitiatives suggested below will have littleeffect, if trained personnel are not available.In the recent past, there has been a relativelysmall number of individuals entering bio-physics, biophysical chemistry, and thegeneral field of structural biology. The ma-jor attraction during that period was clearlymolecular genetics. During the past year ortwo, there has been an increasing numberof entering graduate students interested inquantitative structural studies.

This student interest has coincided witha dramatic upsurge in activity in the indus-trial sector. A substantial number of bio-technology firms have set up structural units,

46

including x-ray crystallography, high-reso-lution NMR, and theoretical modeling. Re-searchers experienced in one or more aspectsof structural biology and general proteinchemistry are in high demand at this time,and corporations have attracted much of thepresently available talent.

Currently available predoctoral trainingprograms may be adequate to provide thenecessary graduate student input to this fieldprovided these predoctoral training programs aremaintained at a level at least equal to their presentlevels. A particularly effective source of highlyqualified personnel is provided by the Med-ical Sdentist Training Program. If there arefurther cuts in any of the programs, thestructure area, which is poised scientificallyfor substantial progress, will be nipped inthe bud, and will suffer proportionally morethan the well-populated areas of molecularand allular biology.

The most serious concern for personnelis postdoctoral training. The new genera-tion of structural biologists must be familiarwith molecular biology as well as biophys-ics, and it would be highly desirable thatmolecular biologists with an interest instructure learn at least the rudiments of thebiophysical methods. Similarly, physicistsand instrumentation engineers whose ex-pertise could be shifted rapidly to structuralbiology must learn some molecular biology.This interdisciplinary training is difficult toaccomplish properly in the time period of anormal doctoral program; postdoctoraltraining thus becomes even more essentialthan usual under these circumstances. Weurge that the postdoctoral fellowship programsbe maintained and, if possible, expanded to coverthe present and anticipated needs in structuralbiology.

3. Supply and Development of MajorInstruments The entire field of structuralbiology is heavily dependent on majorequipment items and on unique facilitiesavailable at certain national centers. Contin-uing progress on the biological problems inthis field will be closely correlated with the

53


improvement and availability of advancedinstrumentation.

X-Rny Diffraction Currently available areadetectors are having an enormous impacton the efficiency of data collection and onthe types of research programs that it is re-alistic to plan. Agencies should be prepared tofund acquisition of area detectors, and ancillaryequipment for efficient utilization, widelythroughout the structural biology community overthe next few years.

The effective use of the synchrotron x-ray sourcesat the national laboratories will depend on thedevelopment of high-flux area detectors capableof recording at least 108 events per second. Ef-forts are under way for other scientific fields;the needs of structural biology should beconsidered as part of this general develop-ment effort.

Nuclear Magnetic Resonance The distri-bution of 500-MHz instruments, or their fu-ture replacements, will continue to presenta policy problem. Laboratories devoted tothe development of NMR techniques, or tomajor long-term protein-structure projects,will need fully dedicated instruments of theirown. Shared facilities should still be dedi-cated to the study of macromolecules andshould not be expected to provide smallmolecule spectra as an additional servicecomponent.

Improvements in resolution and sensitiv-ity will depend on the development ofstronger magnets. Sensitivity and resolu-tion both become increasingly important asthe size of the protein increases, and bothare improved as the magnetic field strengthof the spectrometer is increased. We suggestthat a major effort be launched to interest andencourage instrument companies to producespectrometers with a 17 .5 T (750-MHz) magnet.This appears to be feasible with currentlyavailable superconducting wire technology,although some engineering difficulties re-main to be solved. A magnet at 20-25 T(-1,000 MHz) is not out of the question,although an intensive investigation in thematerials science area may be involved. Suc-

47

cess, however, would have a dramatic im-pact on biophysical NMR studies.

Availability of precursor chemicals la-beled with stable isotopes is another NMRconcern. The very high price of labeled ma-terial is a serious general problem for sci-entists. The Stable Isotope Facility at LosAlamos is bound by regulation to stop anyactivity that is taken up in the private sector.In contrast to many other examples of sci-entific resource supply, this particular reg-ulation has worked to the disadvantage ofthe research community. There is not a suf-ficiently large market for labeled com-pounds to reduce the price through volumeand competition. Even the development ofclinical applications would produce a mar-ket for only a relatively small number ofcompounds and would not cover the broadrange needed for the research proposedabove. It is essential that a mechanism be foundfor providing amino acids and nucleotides witha variety of different stable isotope labeling pat-terns for the research community.

Computers The instrumentation needs fortheoretical and experimental studies of pro-teins include increased and predictable access tosupercomputers; improved communicationsbetween these machines and remote usersthrough networking; and additional accessto high-quality graphics cbwices, scientificworkstations, and speci.71 ourpose com-puters

X-ray crystallograph',.. MR, and theo-retical studies all hav- c heavy com-puting requirements. . larger themolecules and the faster the data collec-tion, the larger will be the computationalrequirements in the immediate future. Evenfor structures of modest size, the currentiterative x-ray refinement procedures cre-ate major inconvenience to other users ofa VAX. (Refinement cycles can occupy tensof hours per cycle.) Protein data process-ing even from current NMR spectrometersrequires levels of computation not nor-mally available in the laboratories of in-dividual investigators. Many theoretical

problems are not at all practical on inter-mediate-level machines.

We estimate that the needs of the currentscientific community in structural biologynationwide may already exceed the com-puting power represented by two ad-vanced-level Cray machines. The presentNational Science Foundation Supercompu-ter Center Program is useful in providingaccess to these machines. This initiative,however, covers all areas of science and maywell become saturated. The necessary phasedexpansion of this program should includethe present and anticipated requirements ofthe structural biologists. A library of pro-grams specifically written to take advantageof the architecture of these machines alsowill be essential for their effective use.

The efficient use of the supercomputerswill depend on the ease and convenience ofaccess. The latter will depend on the speedand effectiveness of the networking that isavailable to make this possible. Networkssuitable for connection of the lower-level

48

computers in the various structure labora-tories also will become increasingly useful.Experience over the next year or two withthe currently developing general purposenetworks will show whether or not they areadequate for this purpose.

A large volume of protein sequence andstructure data can be expected in the nearfuture as a result of the many new metho-dologies. Therefore, it is time to plan for theaccession and use of the data in a comput-erized central data bank. Computer searchesof genetic structure data banks have pro-vided significant new insights into biologi-cal phenomena, and a similar outcome canbe expected from the protein structure data.

Finally, there will be increased need fordedicated microcomputers and various lev-els of graphics workstations in individuallaboratories. Although these are not ex-pected to be particularly expensive, the needfor their wide distribution is clearly visiblenow and should have a prominent place inthe planning for future equipment support.


Prevention and Treatment of Viral Diseases

Research Briefing Panel onPrevention and Treatment of Viral Diseases

Wolfgang K. Joklik (Chairman), DukeUniversity Medical Center, Durham,N.C.

Seymour S. Cohen, State University ofNew York at Stony Brook (retired),Woods Hole, Mass.

William Haseltine, Dana Farber CancerInstitute, Boston, Mass.

Maurice R. Hilleman, Merck Institute forTherapeutic Research, West Point, Pa.

Joseph L. Melnick, Baylor College ofMedicine, Houston, Tex.

Thomas C. Merigan, Jr., StanfordUniversity School of Medicine,Stanford, Calif.

Roland K. Robins, ICN Pharmaceuticals,Inc., Costa Mesa, Calif.

50

Bernard Roizman, University of Chicago,Chicago; Ill.

Julius S. Youngner, University ofPittsburgh School of Medicine,Pittsburgh, Pa.

Staff

Roy Widdus, Director, Division ofInternational Health, Institute ofMedicine

Mark Feinberg, ConsultantAllan R. Hoffman, Executive Director,


57


Prevention and Treatment of Viral Diseases

LNTRODUCTION

Viruses are segments of genetic material,either RNA or DNA, encased in protein shellsand often further wrapped in lipid-contain-ing envelopes. Viruses multiply only withinliving cells, commandeering the host cell tosynthesize their proteins and also their nu-cleic acids.

Infection 7ofoundly affects the host cell,bestowing on it characteristics that distin-guish it from uninfected cells. Viruses dis-rupt or kill infected cells or transk.rm theminto tumor cells, thereby causing disease.Viral diseases vary in severity from mild andtransitory infections to illnesses that termi-nate in death. Persistent viral infection, whichfor years may not be accompanied by symp-toms, can eventually cause chronic degen-erative disease with fatal outcome. Virusescause a wide variety of cancers in animals,and the epidemiologic and laboreory evi-dence is very strong that viruses also causehuman cancer.

Minimizing the harmful effects of viral in-fections has long been a major goal of med-ical and veterinary science. The two majorapproaches to achieving this goal are pre-venting the onset of viral diseases by im-

51

munization (vaccination) and treating viraldiseases by arresting and curing infectionsonce they have started.

PREVENTION ' `F .1JTIAL. DISEASES

Prevention. cf &'iseases is based onthe fact that virascs usually elicit the for-mation of protective or "neutralizing" an-tibodies, cell-mediated immunity, or both.It is therefore possible to protect against viralinfection by immunizationraising a host'simmune defenses ahead of timeso thatwhen the disease-causing virus enters thehost, it is quickly neutralized by antibodies.In conjunction with other components ofthe host's immune system, these antibodiesinactivate, destroy, and eliminate the virus.The immunizing agent may be active virusin the form of a harmless (avirulent) variant,inactivated (killed) virus, or the viral pro-teins that elicit the formation of neutralizingantibody (subunit vaccine). The earliest formof immunization undoubtedly was variola-tion, invented many centuries ago by theChinese, in which persons were exposed toskin scabs from others who had survivedsmallpox infections. The rationale was thatin such cases the disease had been caused

58

by a less virulent form of the variola orsmallpox virus. The pra ctice was danger-ous, with a fatality rate of up to 1 percent,but it did afford a measure of protection.The first example of a "killed" vaccine wasthe rabies vaccine developed by Pasteur. Asfor the subunit approach, many such vac-cines have been devised, but none waswidely used in human beings until a hep-atitis 13 virus subunit vaccine was licensedin the United States in 1981.

Prevention of viral diseases has had someoutstanding successes. Smallpox, one of themost devastating of all infectious agents inhuman beings, has been eradicated globallythrough the use of energetically executedvaccination programs. Yellow fever virus hasalso essentially been eliminated in some partsof the world. Effective control has been es-tablished over poliomyelitis, measles,mumps, and rubella, which until the middleof the twentieth century infected millions ofchildren annually in this country, causingmany deaths and disabling even largernumbers.

TREATMENT OF VIRAL DISEASES

Successful treatment of viral diseases re-quires interruption of virus multiplicationby specifically inhibiting the functioning ofvirus-encoded proteins and nucleic acids.This strategy primarily entails the identifi-cation of analogues of nucleic acid and pro-tein components capable of inhibiting virus-specified reactions to a greater extent thanreactions essential for host cell multiplica-tion and survival.

The approach used so far has been some-what empirical: effective compounds are ei-ther identified by the use of screeningprograms, or progressively more active an-alogues are devised in organic synthesisprograms, Numerous drugs have been foundthat are capable of inhibiting the multipli-cation of a wide variety of viruses in cul-tured cells to a greater extent than they inhibitthe multiplication of the host cells them-

52

selves. Several such drugs (idoxurdine, ri-bavirin, and Acyclovir) have been licensedfor human use.

Empirical approaches are not generallydesigned to yield drugs that are specific in-hibitors of the functions of viral proteins andnucleic acids. Until very recently, most orthe drugs examined have been general in-hibitors of protein and nucleic acid syrv the-sis, and a few happen to inhibit certain viruo-encoded enzymes somewhat more effec-tively than analogous hos',' cell functions.However, investigation of viral multip .a-tion cycles at the molecular level has greatlyexpanded knowledge of the virus-specificprocesses and structures that could serve astargets for antiviral chemotherapy.

TARGET VIRAL DISEASES

Many viral diseases still present graveproblems. The virus that causes acquiredimmune deficiency syndrome (AIDS) is arecently recognized and serious problem, butmany other viruses have long been knownto cause a wide spectru-: of diseases, bothacute and chronic, involving all organ sys-tems of the human body. Diarrheal and re-spiratory disease viruses are probably themajor global cause of morbidity and mor-tality in children, especially in developingcountries. These include rotavirus, parain-fluenza viruses, coronaviruses, and re,;pi-ratory syncytial virus. Influenza virus afflictsall age groups but is most life threateningin the elderly. Other important viruses in-clude hepatitis 13, cytomegalovirus, andherpes simplex. Viruses causing hemor-rhagic fevers oy, encephalitis are often insect-borne and include dengue virus (prevalentin the Caribbean and Southeast Asia) andJapanese B encephalitis virus (prevalet inthe Far East). Poliomyelitis, measles, mumps,and rubella are still widespread in devel-oping countries.

Viruses are suspected of involvement inseveral slow degenerative diseases; exam-ples include Creuizfeldt-Jakob disease, Alz-

59

heimer's disease, and juvenile diabetesmellitus. The same is true for a variety ofhuman malignancies including cervical car-cinoma (certain human papillomaviruses);Burkitt's lymphoma and nasopharyngealcarcinoma (Epstein-Barr virus); liver cancer(hepatitis B virus); and certain human leu-kemias (HTLV-I and -II). Many of these hu-man tumor viruses were discovered in thepast 10 years, and it is expected that morewill be found before long.

In addition to the viruses that affect hu-man beings, there are many others that causedisease in animals and plants, with enor-mous economic loss to agriculture.

In suminary, viruses remain among themajor scourges of mankind. They cause anenormous burden of illness with resultanteconomic loss; they kill and permanentlydisable millions annually both in this coun-try and throughout the world. The objectiveof this report is to illustrate that recent ad-vances in virology and molecular biologyhave pointed the way to new strategies forpreventing and treating viral diseases.

RECENT ADVANCESIN MOLECULAR VIROLOGY

The advent of two technologies duringthe past 15 years has led to greater knowl-edge of the nature of viruses and of theirmultiplication cycles. These are recombi-nant DNA (gene-splicing) technology, whichpermits the isolation and detailed molecularcharacterization of DNA or RNA, and thetechnology for producing monoclonal anti-bodies, which provides reagents not onlyfor specific proteins but also for specific an-tigenic sites on specific proteins. Applica-tion of these methods has provided newinsights into the structure of virus particlesand surface proteins and into the regulationof virus multiplication. Each of these areasoffers different opportunities for combatingviral diseases. The more detailed descrip-tion, below, of advances in each area is fol-lowed for each by identification of the specific

53

research opportunities that could be pur-sued.

THE STRUCTURE OF VIRUS PARTICLES

Great progress has been made in recentyears with respect to knowledge of virusstructure. The three-dimensional structuresof several plant and animal viruses, includ-ing some human pa thogens (e.g., polio-myelitis virus and rhinovirus) have been de-termined. These studies are extremely im-portant in the elucidation of how virusparticles interact with host cells and anti-bodies.

The9e studies on whole virus particles havebeen paralleled by studies of individualcomponents of virus particle surfaces. Twotypes of such components are of funda-mental importance. The first includes theviral cell attachment proteins, which are theproteins that recognize receptors on suscep-tible cells. For instance, certain viruses haveproteins (termed hemagglutinins) that rec-ognize receptors on erythrocytes (red bloodcells) and cause their agglutination. Attach-ment proteins have been identified for a va-riety of viruses, and more recently cellularreceptors also are being identified. An im-portant question is whether these cellularreceptors have some other essential cellularfunction, in addition to the recognition ofviral attachment proteins. Studies of thisquestion and of the role of these receptorsduring virus contact by and penetration ofhost cells are under way. They will providea basis for investigations to determine if theinteraction of viruses with their receptorscould be prevented, inhibited, or termi-nated so as to protect from infection.

The second class of viral surface featuresimportant to the interaction of viruses andorganisms is their antigenic sites, termedepitopes. Here the primary question is whichepitopes elicit the formation of protective orneutralizing antibodies. The surface com-ponents of many types of virus particles havebeen elucidated and the genes that encode

6 0

many of these proteins have been se-quenced, that is, deciphered for the infor-.mation in their basic structural units. In both'cases, studies have included viruses fromall the major classes in these two broad cat-egories. The most intensively sturl'-," -seproteins is the hemagglutinin (Pas; .

enza virus. Not only have the amino acidsequence and three-dimensional structureof the HA of an important influenza strainbeen determined, but variant strains (withdifferent antigenic properdes) also have beensequenced. As a result, it is now knownwhere the important epitopes on the influ-enza virus HA are, what the nature of theantibodies synthesized in response to in-dividual epitopes is, and how single aminoacid changes affect epitope function. Similarstudies are in progress on several other vi-ruses and viral surface components.

SPECIFIC STRATEGIES FORPREVENTING VIRAL DISEASES

Strategies for preventing viral diseaseshave as their goal the neutralization of virusparticles before they can establish produc-tive infection. Among the most interestingapproaches are those discussed below.

GENETICALLY MODIFIED LIVE VIRUSES

The most successful vaccines are thosecontaining attenuated (weakened) live virusparticles. Attenuation is generally achievedby serially culturing the virulent virus in thecells or tissues of some other host, whichoften gives rise to variants that have lostvirulence for human beings. Suitable var-iant strains that still will grow weli enoughin the human host to elicit the formation ofneutralizing antibodies against the disease-causing strain, but that cause neither dis-ease nor untoward reactions, are then se-lected. It has recently become clear thatgenetic engineering techniques could be usedto provide improved attenuated vaccine

54

strains much more rapidly than the slowand relatively uncontrollable process of se-rial culturing.

The genetic material of many viruses hasnow been sequenced, and the genes re-sponsible for specifying the interactions ofthe virus with the host organism are beingmapped. These include the genes respon-sible for determining affinity for particularhost tissues, ability of the virus to spreadfrom one location in the organism to an-other, virulence and nature of cytopathic ef-fects, capacity to establish latent or persistentinfection, and immunogenicity. A wide va-riety of genetic techniques are available toidentify and manipulate such genes. Oncethe genes governing virulence or other fac-tors have been identified and characterized,they can b? altered or inactivated relativelysimply. In this manner, it should be possibleto provide a new generation of acceptablysafe vaccine virus strains.

THE USE OF VIRUS VECTORS

The genes for many proteins capable ofeliciting the formation of neutralizing anti-bodies have been isolated. Such genes de-rived from virulent disease-causing virus canbe inserted into avirulent vectors such asvaccinia virus or adenovirus. When thesevectors are used to infect hosts (withoutcausing disease), the inserted foreign genesare expressed, and the host develops anti-bodies and immunity to the viir, from whichthey were derived. The feasibility of this ap-proach has been demonstrated: a vector car-rying the major rabies virus glycoprotein hasbeen used successfully to protect foxesagainst challenge with wild virus. Work isneeded to optimize the safety and efficiencyof the vectors.

PURIFIED VIRAL PROTEINS AS ANTIGENSFOR VACCINES

When individual proteins that elicit theformation of neutralizing antibodies were

61

PREVENTION AND TREATMENT OF VIRAL DISEASES

first identified, attempts were begun to usethem as subunit vaccines. Until recently themajor difficulty was the inability to isolatesufficiently large amounts of the proteins ina state of sufficient purity. Molecular clon-ing techniques have greatly improved thefeasibility of this approach. Genes for viralproteins (such as those for protective anti-gens) can now be inserted into a variety ofprokaryotic and eukaryotic expression vec-tors. These vectors can be introduced intobacterial, yeast, or mammalian cells wherethey can be made to induce the synthesisof large amounts of the specific proteins ac-cording to instructions coded by the in-serted viral gene. These viral proteins couldthen be purified in large quantities and usedas safe and specific vaccines.

DEVELOPMENT OF TECHNOLOGIES FORENHANCING IMMUNOGENICITY

An important aspect of antibody forma-tion is the optimal presentation of antigensto the immune system. Recent advances inimmunology have suggested several newways of improving such presentation.Among possible approaches are the use ofprotein conjugates or aggregates, lipo-somes, or immunostimulatory complexesproduced with plant extracts.

STRATEGIES FOR THE TREATMENTOF VIRAL DISEASES

Strategies for the treatment of viral dis-eases have as their aim the interruption ofviral infections once they have started, re-sulting in the elimination of the virus fromthe body and a cure of the disease. This aimcan be addressed best with detailed knowl-edge of the key reactions of viral multipli-cation cycles. Such reactions are catalyzedby virus-specified enzymes engaged in sub-tle interactions of viral and cellular proteinsand nucleic acids. In the case of envelopedviruses, interactions of viral and cellularproteins with lipid membranes are also of

55

crucial importance. In recent years, techni-cal advances provided by recombinant DNAtechnology and the availability of mono-clonal antibodies have led to a dramatic in-crease in knowledge of the processesinvolved in virus multiplication and the in-teraction of viruses with their host cells. Thefollowing is an outline of current knowledgeabout virus multiplication and of the op-portunities to inhibit it.

THE VIRAL MULTIPLICATION CYCLE

Viruses multiply by means of preciselyregulated series of reactions. Typically, vi-ruses adhere to host cells via specific recep-tors and are internalized by a process ofengulfment (phagocytosis). The viral ge-nome (its DNA or RNA) is then liberatedfrom its protective protein coat, and the viralgenetic information is expressed throughmessenger RNAs that are translated intoproteins. Viruses vary in their complexity;thus the number of proteins encoded by vi-ruses varies: some encode fewer than 10,others more than 100. Subsequently the viralnucleic acid replicates, and the newly rep-licated (progeny) viral genomes are en-closed within newly formed protein coats.The number of progeny virus particlesformed in a cell may vary from a few hundredto more than 100,000. Progeny virus parti-cles are liberated either when the host celldisintegrates or when virus particles "bud"through the cell membrane, thereby acquir-ing their envelopes.

Strategies for the Expression of ViralGenetic Information

One of the key steps in viral multiplica-tion is the expression of the genetic infor-mation encoded in the viral genome. Toachieve this, different viruses use differentstrategies. The genetic information of sin-gle-stranded RNA viruses is translated intoproteins either directly or through the in-volvement of a second messenger strand of

62

RNA complementary to the genome. Thelatter process involves a virus-encoded en-zyme present in the virus particle. RNA vi-ruses containing double-stranded RNA mustalso first be transcribed into messenger RNAby virus-encoded enzymes present in virusparticles.

RNA viruses also include the retroviruses.Upon infection, their RNA is transcribed bya virus-encoded RNA-dependent DNA po-lymerase (reverse transcriptase) into double-stranded DNA (the provirus). Another uniqueenzyme newly translated from the viral RNAintegrates this provirus into the host cell nu-cleic acid. The integrated provirus directs hostcell enzymes in the synthesis of viral proteinsand viral RNA, from which new progeny vi-ruses are assembled.

DNA-containing viruses can only expresstheir genetic information by its being tran-scribed into messenger RNA. Some use hostenzymes for this purpose; others specify theirown DNA-dependent RNA polyrnerases.

Strategies for the Replication ofViral Genetic Material

Viruses employ various strategies for rep-licating their genetic material just as they dovarious strategies for expressing it. The rep-lication of all RNA viruses except retrovi-ruses involves virus-encoded enzymesbecause uninfected cells do not possess en-zymes capable of replicating RNA. The rep-lication of DNA genomes is accomplishedeither by host cell DNA polymerases, or byvirus-encoded DNA polymerases.

OPPORTUNITIES FOR INTERFERING WITH THE

VIRAL GROWTH CYCLE

Recent advances in molecular virologyhave led to the following picture of viruses.Their genomes comprise both regulatory re-gions and coding regions. The regulatoryregions include sequences that serve to reg-ulate a variety of processes, such as nucleicacid and protein synthesis and virus assem-

56

bly, in a variety of ways (e.g., recognition,initiation, promotion, enhancement, andtermination). These regulatory regions ofviral nucleic adds may function by inter-acting with proteins or by interacting withother nucleic acid sequences. The coding re-gions encode virus-specified proteins. Viralproteins are of three kinds: (1) structuralcomponents of virus particles, (2) enzymes,and (3) regulatory proteins that interact withnucleic acids or other proteins.

Numerous opportunities exist for inhibit-ing virus multiplication. One approach is toinhibit the activity of some viral enzymes; an-other is to disrupt the action of some regu-latory protein; and a third is to interfere withthe function of a regulatory nucleic acid se-quence. Sudi approaches are made possibleby the fact that the nucleic acid of many vi-ruses has now been molecularly doned andsequenced. As a result, not only are the se-quences of many viral proteins now known,but also the sequences of many regions ofnucleic acid with regulatory functions.

The following appear to be feasible strat-egies for inhibiting virus multiplication.

Inhibition of Virus-Encoded Enzymes

Nucleic Acid Synthesis Inhibition of viralnucleic acid synthesis would interrupt viralmultiplication and infection. The feasibilityof this approach is confirmed by the fact thatmost successful anthriral compounds cur-rently licensed (e.g., Acyclovir) or under in-vestigation are nudeotide analogues. Becausehost and viral enzymes differ in their abilityto use these compounds as substrates, they(or their metabolites) are preferentially in-corporated into viral nucleic acids and haltmultiplication. Virus-encoded enzymes ofnucleic acid synthesisthe RNA and DNApolymerasesare, therefore, the most ob-vious targets for antiviral chemotherapy.Many, like the RNA-dependent RNA poly-merases, have no counterpaits in unin-fected cells. Now that genes for many of theviral enzymes of nucleic acid synthesis have

63


been cloned, it will soon be possible to pre-pare them in large amounts. When thestructures of the enzymes' catalytic sites havebeen determined, it should be possible todesign compounds, possibly nucleotide an-alogues, that irreversibly inhibit them spe-cifically.

Proteases These enzymes catalyze reac-tions essential to viral multiplication. Manyviral proteins are synthesized in the form ofprecursors, usually 20 to 50 percent largerthan the functional proteins. Sometimesseveral proteins are synthesized linked to-gether in the form of a polyprotein. Precur-sors and polyproteins are cleaved by highlyspecific virus-encoded proteases to activeindividual proteins. Proteases are, there-fore, potential targets for antiviral chemo-therapy.

Capping Enzymes Several viruses encodeenzymes that form caps (modified singlenucleotide additions) at the end of messen-ger RNA molecules that are essential to theefficient functioning of these molecules. Theviral cap-synthesizing enzymes are analo-gous to corresponding host cell enzymes,but their amino acid sequences are likely tobe quite different. Therefore, they representa unique target for intervention.

Integrases The genomes of several typesof virus are inserted into host cell DNA asan essential part of the virus life cycle. Usu-ally, but not invariably, this is the first stepof transforming normal cells into tinnor cells.Some viruses use host cell enzymes for thispurpose, but others, such as the retrovi-ruses, encode their own integrase enzymefor this purpose. These enzymes apparentlyare not capable of recognizing unique cel-lular DNA sequences; but often the nucleicacid segments that are integrated, such asretroviral proviruses, possess highly dis-tinctive features recognized by integrases.This recognition feature of integrases pre-sents a target for antiviral chemotherapy.

57

Sequence-Specific Nucleases Virus-en-coded, sequence-specific nucleases performessential functions during viral genome rep-lication; that is, they cut nucleic acids at pre-cisely specified positions. Again, theserepresent a selective target.

Inhibition of Interactions of Viral and HostCell Proteins with Regulatory Sequences in

Viral Genomes

Precise regulation is essential to the com-plex process of viral multiplication. Most, ifnot all, regulatory regions in viral genomesoperate through interaction with proteinsthat have the ability to recognize and inter-act with specific nucleic acid sequences (i.e.,they are sequence-specific binding pro-teins). Such highly specific nucleic acid-pro-tein interactions promise to be targets forantiviral chemotherapy, but present rudi-mentary knowledge of these interactionsmake this a long-term approach. Two strat-egies can be imagined. First, it is now be-coming feasible to identify the regions ofproteins that bind to nucleic acids. From suchproteins, it may be possible to isolate pep-tides that retain nucleic acid binding abilityand to use either these peptides, or ana-logues that bind even more strongly, to sat-urate the regulatory sequences, thusrendering them unavailable to the func-tional viral proteins. The second approachwould be to use short complementary nu-cleic acid sequences to saturate the regula-tory sequences.

Interference with Messenger RNA Function

Translation of viral genetic information,by means of messenger RNA (mRNA), intoproteins is essential to viral multiplication,and for this the mRNA must be accessibleto the protein-synthesizing machinery as asingle-stranded RNA. Through genetic en-gineering techniques, it is possible to syn-thesize RNA segments that arecomplementary to mRNA and that bind to

it, blocking translation. The present ques-tion regarding this approach is how to in-troduce the inhibitory RNA into cells.However, new ideas are constantly beingconceptualized and evaluated experimen-tally. Thus, this may be a feasible long-termapproach to antiviral chemotherapy.

The Target-Cell Approach

A major concern of antiviral chemother-apy is that even in the most severe diseasesonly a very small fraction of cells in an or-ganism are infected. Clearly it would be ad-vantageous to aim the antiviral agent at theinfected cell rather than to introduce it intoevery cell. Attention has therefore been di-rected at various forms of a target-cell ap-proach to antiviral chemotherapy. At leastthree strategies are being explored. The firstand most attractive is exemplified by a strat-egy that is feasible in cells infected with some,but not all, herpesviruses. These viruses en-code an enzyme, a deoxypyrimidine kinase,that phosphorylates nucleoside analogues(such as Acyclovir) not readily phosphoryl-ated by the analogous host cell enzyme (thy-midine kinase). Such phosphorylatednucleoside analogues are then incorporatedinto viral DNA and inhibit virus multipli-cation. (Phosphorylation of nucleosides is aprerequisite for incorporation into viralDNA.) The attractive feature of this ap-proach is that the antiviral nucleoside ana-logues are not phosphorylated in uninfectedcells and therefore only exert their inhibi-tory effects in infected cells.

The second target-cell approach takes ad-vantage of the fact that virus-encoded pro-teins are incorporated into the membranesof infected host cells soon after infection.Monoclonal antibodies against such pro-teins can be produced and coupled to in-hibitors of nucleic acid or protein synthesisthat would normally not enter cells. Whencombined with antibody molecules, how-ever, they are internalized. Thus, nonspe-cific inhibitors of nucleic acid and protein

58

synthesis can be introduced specifically intoinfected cells.

The third target-cell approach is predi-cated on the fact that soon after infectionthe permeability of the cell membrane oftenincreases, potentially permitting the entryof compounds that would be excluded fromuninfected cells.

Several other strategies for inhibiting viralinfections can be envisaged. Possible strat-egies include direct inhibition of virus-en-coded regulatory proteins, inhibition of theinteraction of viruses with their cellular re-ceptors, inhibition of the budding processfor the release of enveloped viruses frominfected cells, inhibition of viral proteinglycosylation (addition of sugar residues),and inhibition of the intracellular trans-port of viral proteins. The research nec-essary to determine the feasibility of thesestrategies can now be outlined in some de-tail.

THE NEED FOR IMPROVEDTECHNIQUES TO DIAGNOSE VIRAL

INFECTIONS

There is a pressing need for ways to rap-idly diagnose viral infections. Treatment witha specific antiviral agent cannot be selectedbefore thil infecting virus is identified. Re-cent advances in biotechnology such as nu-cleic acid probe techniques and monoclonalantibodies have enhanced capabilities in thisarea, and excellent progress has been madeon some problems, such as determining ex-posure to the virus that causes AIDS. Thelikely availability of effective antiviral drugsshould provide a stimulus to the develop-ment of diagnostic tools.

SELECTED OPPORTUNITIES AMONGVIRAL DISEASES

The following viral diseases are high-priority areas for research into their preven-tion and treatment.

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ACQUIRED IMMUNE DEFICIENCYSYNDROME (AIDS)

The severity of the AIDS problem war-rants major efforts in prevenEon and treat-ment, but immediate prospects for eitherare not highly promising. In this circum-stance a number of approaches should bepursued, and research on pathogenesis ofthe disease should be actively continued. Itis not yet clear how best to approach thedevelopment of a vaccine to prevent AIDS.Among questions to be answered arewhether antibodies to the major viral sur-face protein can be protective, the signifi-cance of the genetic variability of the virus,and why natural infection does not elicitprotective antibodies.

Control of the persistent infection oc-curring with the AIDS virus is also prob-lematic; drugs designed against it mighthave to be taken for extended periods. Thevirus encodes three enzymes, known fora number of years to exist in other retro-viruses but not yet characterized: a reversetranscriptase, an in tcgrase, and A pro-tease. All of these are obvious N,Itry_ t n forrational drug design0forts along 4it wonewly identified regulatory proteins, c,ncethe AIDS provirus has been integrated ill tothe host cell DNA, drugs directed againstany of these targets might have to be takenfor the lifetime of the patient to preventthe spread of the virus, if the virus werenot eliminated from the body by the drug.It is likely that this approach would onlybe practical and feasible if a strategy oftargeting infected cells were adopted.Measures to remove the AIDS provirus fromthe genome of infected cells cannot yet beformulated.

Further specific recommendations willbe made in the report of the NationalAcademy of Sciences-Institute of MedicineCommittee on a National Strategy for AIDS,planned for publication in September 1986.

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INFLUENZA VIRUSES

The optimal strategy for protection againstinfluenza viruses would be a safe and et"fective vaccine, and new approaches areconstantly being tested. In addition, drugsagainst influenza virus would be desirablewhen new virus strains pathogenic for hu-mans appear, before adequate amounts ofnew vaccine can be prepared. Targets foranti-influenza virus chemotherapy are anRNA-dependent RNA polymerase and aunique "cap stealing" protein involved innucleic acid synthesis. Similar considera-tions apply to disease caused by respiratorysyncytial virus and the parainfluenzavi-ruses, which are also important humanpathogens.

HERPES SIMPLEX VIRUSES (HSV) 1 AND 2

A few groups are pursuing various (sub-unit and genetically engineered attenuated)approaches to development of a vaccine toprevent this disease. However, because la-tent infections can give rise to recurrence ofsymptoms even in the presence of antibody,a vaccine may not prevent infection but ratherreduce the severity of initial lesions, theirrecurrences, and possibly their frequency.

Intensive, long-term research will be nec-essary to devise ways to eliminate latent vi-rus once infection has occurred. However,herpes simplex virus (HSV) presents nu-merous targets for antiviral drugs to treatthe lesions and other symptoms that occurwith the initial infection and its recurrences.The best is probably deoxypyrimidine ki-nase, which invites the target-cell approachdescribed above; progressively more effec-tive nucleoside analogues (that function likeAcyclovir) are constantly being synthesized.Other good targets are provided by the DNApolymerase and ribonucleotide reductase thatare encoded by these viruses.

HSV 1 and 2 can serve as models for con-trolling human infections with other her-pesviruses (cytomegalovirus, Epstein-Barr

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virus, and varicella-zoster virus). However,each of these presents unique epidennio-logic, economic, and disease problems.Probably the most costly in terms of per-centage of total health costs are cytomega-lovirus infections in immunocompromisedpeople, such as transplant recipients, andin pregnant women, leading to mental anddevelopmental retardation of their off-spring. Epstein-Barr virus in the United Statesis associated with disseminated mild to se-vere infections of young adults (mononu-cleosis), severe infections in hnmuno-compromised individuals, and fulminatinglethal infections in a small number of chil-dren. Outside the United States it is asso-ciated with certain malignancies includingnasopharyngeal cancer. Varicella-zoster vi-rus is the agent of chickenpox in childrenand shingles in adults.

For all these herpesviruses, specific strat-egies can be devised for vaccines or antivir-als; for example, a vaccine for varicella-zostershould be genetically engineered so that thegenes that enable it to initiate latent infec-tions (that may result in shingles) are re-moved.

9EPATITIS B VIRUS (HBV)

Work 2, millions of people are carriersof hepatitis B virus (HBV); that is, they arepersistently and chronically infected with thisvirus. Each year 800,000 persons, mostly indeveloping countries, die of the conse-quences of HBV infection (cirrhosis and livercancer). For these persons, antivirals wouldbe helpful, and HBV encodes a unique DNApolymerase that would be an excellent tar-get for chemotherapy. For those not yet in-fected, HBV is highly amenable to newvaccine development approaches; a plasma-derived vaccine is available but expensive.The surface antigen of HBV has been clonedand can be expressed in yeast cells. In highlypurified form, it is being tested for its abilityto elicit the formation of neutralizing anti-bodies. Another promising approach to the

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prevention of HBV infection is the insertionof the gene for the HBV surface antigen intoa vector virus such as vaccinia virus. Im-munization of newborns is the favored pre-vention strategy in areas of high incidenceof disease.

ROTA VIRUSES

Rotaviruses are an important cause ofdiarrheal disease and infant mortc!lityworldwide. Both the antiviral drug ap-proach and the vaccine approach appear tobe promising. The rotavirus multiplicationcycle involves two different RNA-depen-dent RNA polymerases, which are thereforegood targets for antiviral chemotherapy.

Some rotavirus vaccine candidates are indevelopment, such as those based on bo-vine or rhesus rotaviruses; other candidateshave been developed through genetic reas-sortment techniques. However, the genesthat encode rotavirus surface antigens havebeen cloned and are now being placed intoexpression systems. Thus, it may also bepossible soon to prepare large amounts ofthe surface antigen(s) for use as a better de-fined, highly specific, and safe rotavirussubunit vaccine.

OTHER VIRUSES

A large number of other viral diseases areknown; it should soon be possible to de-velop vaccines or antivirals to prevent ortreat many of them. Among the most im-portant are human papillomavirus, certaininsect-borne viruses, hepatitis A virus, andadult T-cell leukemia virus.

IMPLEMENTING STRATEGIES FORDEVELOPMENT OF NEW VACCINES

AND ANTIVIRALS

Pursuing the above approaches to the de-sign of new viral vaccines and specific an-tiviral drugs is a long-term program. Al-

67


though the required principles are known,much remains to be done in the course ofdeveloping these approaches to yield prac-tical vaccines or drugs. Their theoretical ba-sis, however, is firm and their prospectshighly promising.

Pursuit of prevention or treatment mo-dalities should not be regarded as mutuallyexclusive efforts. Useful cross-fertilizationoccurs between the two activities. Treat-ment may be needed to "backstop" even ahighly successful prevention effort, or it maybe a more rational approach for some dis .

eases where a target population for vacci-nation is presently difficult to identify.

In spite of the high likelihood of successin this area, there are several impedimentsto its realization. The major problems thatneed to be addressed are as follows.

1. The development of highly specific andpotent antiviral drugs requires the collabo-ration of scientists in several disciplines,among them protein chemists, enzyme ki-neticists, biophysicists, x-ray crystallogra-phers, organic chemists, virologists, cellbiologists, pharmacologists, toxicologists,and clinicians. Not all such scientists wouldhave to interact at the same time; but in theinitial phases of the work, protein chemists,enzyme Idneticists, biophysicists, and or-ganic chemists will have to interact quiteclosely. A coordinated national effort isneeded and should involve extensive col-laboration among components of the entirescientific community. Such collaboration maycome about through the cooperation of sci-entists in various disciplines on the sameuniversity campus, among several univer-sity campuses, within private companies,between universities and companies, andbetween all these groups and governmentscientists.

2. To capitalize on the opportunities thatexist, there is a need to invigorate public-private partnerships. Private industry isconcerned about the confidentiality of thresults that are obtained because confiden-

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tiality is essential for the protection of patentrights, which are needed to recoup high de-velopment costs. Close, long-term collabo-ration between scientists in universities andtheir counterparts in industry would behighly desirable, but such cooperation willrequire very careful management and mayalso require the development of new mech-anisms of promoting and funding it.

3. A serious impediment is the threat ofpossible liability for inadvertent injuries at-tributed to vaccines. A system providingcompensation to individuals who incur un-toward injury from vaccines tha, are cor-rectly manufactured and administered isessential, along with some means of defin-ing much more clearly than is currently thecase the limits of manufacturers' liabilities.*

4. Another major impediment is currentuncertainty about the legal limits of appli-cability of recombinant DNA research. A vo-cal minority persists in opposing any kindof innovation resulting from the applicationof recombinant DNA technology to humanhealth. There is a need for more public ed-ucation on the nature, benefits, risks, andpractical capabilities of recombinant DNAtechnology. Within their mandates, agen-cies should attempt to provide guidance onthese issues to interested partiesfor ex-ample, potential manufacturers and "con-sumers" of products.

In the final analysis, the usefulness of an-tiviral drugs and vaccines should be judgedon the basis of the net benefits they provide;absolute safety should not necessarily andinvariably be the goal. Evaluations shouldtake into account the number of lives saved,the misery spared, and the economic ben-efits accrued as well as known and potentialrisks.

*See Vaccine Supply and Innovation, a report from theInstitute of Medicine, National Academy of Sciences,published by the National Academy Press, Washing-ton, D.C., 1985.

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BENEFITS OF A NATIONAL EFFORTON VACCINES AND ANTIVIRALS

Control of poliomyelitis, meas1.2s, mumps,and rubella in the United 3tates has pro-duced annual savings esenated in 1950 at$2 billion. The benefits of the strategies en-visaged above would be the further savingsof many lives and the enormous reductionof misery and costs attributable to acute dis-ease or to persistent, latent, and chronic in-fections that later cause degenerative diseasesor cancer. Additional viral diseases shouldbe eradicated following the example ofsmallpox.

The capabilities dew. ,.3ped in a programon human viral diseases would also be ap-plicable to viral diseases of livestock andpoultry, where economic losses of produc-tion are enormous.

SUMMARY AND CONCLUSIONS

Recent advances in molecular virologyhave laid the foundation for combating manyviral diseases through new vaccines or moreranal approaches to the development of

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antiviral drugs. These new approaches uti-lize recent advances in the knowledge ofviral surfaces and of unique processes en-coded by viral nucleic acid. A central featureof the approaches to antivirals is the selec-tion, as targets, of processes that are essen-tial to viral multiplication but for which nohost cell counterpart exists. While this is aprogram area in which timely addition ofemphasis and support would pay great div-idends, certain organizational difficulties(such as the need for large collaborative ef-forts) and policy issues (such as liability forvaccine injury) will need to be addressed toensure the realization of the great healthand economic benefits that these new tech-nologies promise.

ACKNOWLEDGMENT The committee grate-fully acknowledges the assistance of the follow-ing individuals in the preparation of thisdocument: Donald S. Burke, Walter Reed ArmyInstitute of Research; Joel M. Dalrymple, U.S.Army Institute for Infectious Diseases; BernardMoss, National Institutes of Health; Michael Lai,University of Southern California; Stephen E.Straus, National Institutes of Health.

NationaC Acculaty livssThe National Academy Press was created by the National Academy ofSciences to publish the reports issued by the Academy and by theNational Academy of Engineering, the Institute of Medicine, and theNational Research Council, all operating under the charter granted tothe National Academy of Sciences by the Congress of the United States. ISBN 0-309-03689-5

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