Buy ebook Large Scale Biomedical Science Exploring Strategies for Future Research 1st Edition Committee On Large-Scale Science And Cancer Research cheap price

Download the full version of the ebook at
https://ebookultra.com
Large Scale Biomedical Science Exploring

Strategies for Future Research 1st Edition
Committee On Large-Scale Science And Cancer
Research
https://ebookultra.com/download/large-scale-
biomedical-science-exploring-strategies-for-
future-research-1st-edition-committee-on-large-
scale-science-and-cancer-research/
Explore and download more ebook at https://ebookultra.com

Recommended digital products (PDF, EPUB, MOBI) that
you can download immediately if you are interested.
Large Scale Geometry Second Edition Piotr Nowak
https://ebookultra.com/download/large-scale-geometry-second-edition-
piotr-nowak/
ebookultra.com
Creativity In Large scale Contexts 1st Edition Jonathan S.

Feinstein
https://ebookultra.com/download/creativity-in-large-scale-
contexts-1st-edition-jonathan-s-feinstein/
ebookultra.com
Mastering Kubernetes Large scale container deployment and

management 1st Edition Gigi Sayfan
https://ebookultra.com/download/mastering-kubernetes-large-scale-
container-deployment-and-management-1st-edition-gigi-sayfan/
ebookultra.com
Large Scale Software Architecture A Practical Guide using

UML 1st Edition Garland
https://ebookultra.com/download/large-scale-software-architecture-a-
practical-guide-using-uml-1st-edition-garland/
ebookultra.com
Large Scale Solar Thermal Power Technologies Costs and
Development 23rd Edition Werner Vogel
https://ebookultra.com/download/large-scale-solar-thermal-power-
technologies-costs-and-development-23rd-edition-werner-vogel/
ebookultra.com
Large Scale Ecology Model Systems to Global Perspectives

1st Edition Alex J. Dumbrell
https://ebookultra.com/download/large-scale-ecology-model-systems-to-
global-perspectives-1st-edition-alex-j-dumbrell/
ebookultra.com
Emergent semantics interoperability in large scale

decentralized information systems 1st Edition Philippe
Cudre-Mauroux
https://ebookultra.com/download/emergent-semantics-interoperability-
in-large-scale-decentralized-information-systems-1st-edition-philippe-
cudre-mauroux/
ebookultra.com
Subverting Borders Doing Research on Smuggling and Small

Scale Trade VS Research 2012th Edition Bettina Bruns
https://ebookultra.com/download/subverting-borders-doing-research-on-
smuggling-and-small-scale-trade-vs-research-2012th-edition-bettina-
bruns/
ebookultra.com
Energy From the Desert Practical Proposals for Very Large

Scale Photovoltaic Systems v 2 Kosuke Kurokawa
https://ebookultra.com/download/energy-from-the-desert-practical-
proposals-for-very-large-scale-photovoltaic-systems-v-2-kosuke-
kurokawa/
ebookultra.com
Large Scale Biomedical Science Exploring Strategies for
Future Research 1st Edition Committee On Large-Scale
Science And Cancer Research Digital Instant Download
Author(s): Committee on Large-Scale Science and Cancer Research, National
Research Council, Sharyl J. Nass, Bruce W. Stillman
ISBN(s): 9780309089128, 0309089123
Edition: 1
File Details: PDF, 5.80 MB
Year: 2003
Language: english
http://books.nap.edu/catalog/.html
Committee on Large-Scale Science and Cancer Research

Sharyl J. Nass and Bruce W. Stillman, Editors
National Cancer Policy Board
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
and
Division on Earth and Life Studies
THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu
Copyright © 2003 National Academy of Sciences. All rights reserved.

Unless otherwise indicated, all materials in this PDF File provided by the National Academies Press (www.nap.edu) for research
purposes are copyrighted by the National Academy of Sciences. Distribution, posting, or copying is strictly prohibited without
written permission of the NAP.
Generated for [email protected] on Tue Jul 15 05:46:27 2003
THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, N.W. • Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Governing Board
of the National Research Council, whose members are drawn from the councils of the
National Academy of Sciences, the National Academy of Engineering, and the Institute of
Medicine. The members of the committee responsible for the report were chosen for their
special competences and with regard for appropriate balance.
Support for this project was provided by The National Cancer Institute. The views pre-
sented in this report are those of the Institute of Medicine and National Research Council
Committee on Large-Scale Science and Cancer Research and are not necessarily those of the
funding agencies.
Library of Congress Cataloging-in-Publication Data
Large-scale biomedical science : exploring strategies for future

research / Sharyl J. Nass and Bruce W. Stillman, editors ; Committee on
Large-scale Science and Cancer Research, National Cancer Policy Board
and Division on Earth and Life Studies, National Research Council.
p. ; cm.
Includes bibliographical references.
ISBN 0-309-08912-3 (pbk.) — ISBN 0-309-50698-0 (PDF)
1. Medicine—Research—Government policy—United States. 2.
Cancer—Research—Government policy—United States. 3. Federal aid to
medical research—United States.
[DNLM: 1. Biomedical Research—United States. 2. Interinstitutional
Relations—United States. 3. Research Design—United States. 4.
Resource Allocation—United States. W 20.5 L322 2003] I. Nass, Sharyl
J. II. Stillman, Bruce. III. National Cancer Policy Board (U.S.).
Committee on Large-scale Science and Cancer Research. IV. National
Research Council (U.S.). Division on Earth and Life Studies.
R854.U5L37 2003
610'.7’2073—dc21
2003009162
Additional copies of this report are available from the National Academies Press, 500 Fifth
Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the
Washington metropolitan area); Internet, http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page at: www.
iom.edu.
Copyright 2003 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America.

The National Academy of Sciences is a private, nonprofit, self-perpetuating soci-

ety of distinguished scholars engaged in scientific and engineering research, dedi-
cated to the furtherance of science and technology and to their use for the general
welfare. Upon the authority of the charter granted to it by the Congress in 1863,
the Academy has a mandate that requires it to advise the federal government on
scientific and technical matters. Dr. Bruce M. Alberts is president of the National
Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter
of the National Academy of Sciences, as a parallel organization of outstanding
engineers. It is autonomous in its administration and in the selection of its mem-
bers, sharing with the National Academy of Sciences the responsibility for advis-
ing the federal government. The National Academy of Engineering also sponsors
engineering programs aimed at meeting national needs, encourages education
and research, and recognizes the superior achievements of engineers. Dr. Wm. A.
Wulf is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of

Sciences to secure the services of eminent members of appropriate professions in
the examination of policy matters pertaining to the health of the public. The
Institute acts under the responsibility given to the National Academy of Sciences
by its congressional charter to be an adviser to the federal government and, upon
its own initiative, to identify issues of medical care, research, and education. Dr.
Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sci-
ences in 1916 to associate the broad community of science and technology with
the Academy’s purposes of furthering knowledge and advising the federal gov-
ernment. Functioning in accordance with general policies determined by the Acad-
emy, the Council has become the principal operating agency of both the National
Academy of Sciences and the National Academy of Engineering in providing
services to the government, the public, and the scientific and engineering commu-
nities. The Council is administered jointly by both Academies and the Institute of
Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair,
respectively, of the National Research Council.
www.national-academies.org

COMMITTEE ON LARGE-SCALE SCIENCE

AND CANCER RESEARCH
*JOSEPH V. SIMONE, M.D. (Chair), Simone Consulting,

Dunwoody, GA
*BRUCE W. STILLMAN, Ph.D. (Vice Chair), Director, Cold Spring
Harbor Laboratory, Cold Spring Harbor, NY
*ELLEN STOVALL (Vice Chair), Executive Director, National
Coalition for Cancer Survivorship, Silver Spring, MD
*DIANA PETITTI, M.D. (Vice Chair), Director, Research and
Evaluation, Kaiser Permanente of Southern California,
Pasadena, CA
*JILL BARGONETTI, Ph.D. Associate Professor, Hunter College,
New York, NY
BARRY BOZEMAN, Ph.D. Regents Professor of Public Policy,
Director of the State Data and Research Center, Georgia Institute
of Technology, Atlanta, GA
*TIM BYERS, M.D., M.P.H. Professor of Epidemiology and
Associate Director, University of Colorado Cancer Center,
University of Colorado School of Medicine, Denver, CO
TOM CURRAN, Ph.D. Chairman of the Department of
Developmental Neurobiology, St. Jude’s Children’s Research
Hospital, Memphis, TN
*TIMOTHY EBERLEIN, M.D. Bixby Professor and Chairman,
Washington University School of Medicine, Department of
Surgery, St. Louis, MO
DAVID GALAS, Ph.D. Chief Academic Officer and Norris
Professor of Applied Life Sciences, Keck Graduate Institute of
Applied Life Sciences, Claremont, CA
*KAREN HERSEY, J.D. Senior Intellectual Property Counsel, Office
of Intellectual Property Counsel, Massachusetts Institute of
Technology, Cambridge, MA
*DANIEL J. KEVLES, Ph.D. Professor, Yale University, Department
of History, New Haven, CT
LAUREN LINTON, Ph.D., M.B.A. President, Linton Consulting,
Lincoln, MA
*WILLIAM W. MCGUIRE, M.D. Chairman and Chief Executive
Officer, UnitedHealth Group, Minnetonka, MN
*JOHN MENDELSOHN, M.D. President, University of Texas, M.D.
Anderson Cancer Center, Houston, TX
iv
*KATHLEEN H. MOONEY, Ph.D. Professor and Peery Presidential

Endowed Chair in Nursing Research, University of Utah College
of Nursing, Salt Lake City, UT
*NANCY MUELLER, Sc.D. Professor of Epidemiology, Harvard
School of Public Health, Department of Epidemiology, Boston,
MA
*PATRICIA A. NOLAN, M.D., M.P.H. Director, Rhode Island
Department of Health, Providence, RI
*CECIL B. PICKETT, Ph.D. Executive Vice President, Discovery
Research, Schering Plough Institute, Kenilworth, NJ
STEPHEN PRESCOTT, M.D. Executive Director H.A. and Edna
Benning Presidential Chair in Human Molecular Biology and
Genetics, Huntsman Cancer Institute, University of Utah, Salt
Lake City, UT
*LOUISE B. RUSSELL, Ph.D. Research Professor of Economics,
Institute for Health, Rutgers University, New Brunswick, NJ
*THOMAS J. SMITH, M.D., F.A.C.P. Professor, Medical College of
Virginia at Virginia Commonwealth University, Division of
Hematology, Richmond, VA
*SUSAN WEINER, Ph.D. President, The Children’s Cause, Silver
Spring, MD
*ROBERT C. YOUNG, M.D. President, American Cancer Society
and the Fox Chase Cancer Center, Philadelphia, PA
STUDY STAFF
SHARYL J. NASS, Ph.D. Study Director
ROGER HERDMAN, M.D. Director, National Cancer Policy Board
MARYJOY BALLANTYNE Research Associate
NICCI DOWD Administrative Assistant (through January 2003)
NAKIA JOHNSON Project Assistant (from February 2003)
*Members of the National Cancer Policy Board, Institute of Medicine, The National
Academies.
v
REVIEWERS
This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with pro-
cedures approved by the NRC’s Report Review Committee. The purpose
of this independent review is to provide candid and critical comments
that will assist the institution in making its published report as sound as
possible and to ensure that the report meets institutional standards for
objectivity, evidence, and responsiveness to the study charge. The review
comments and draft manuscript remain confidential to protect the integ-
rity of the deliberative process. We wish to thank the following individu-
als for their review of this report:
Mina J. Bissell, Ph.D. Distinguished Scientist, Life Sciences

Division, Lawrence Berkeley National Laboratory
Marvin Cassman, Ph.D. Director, QB3 at University of California,
San Francisco
Mildred Cho, Ph.D. Senior Research Scholar and Acting Co-director,
Stanford Center for Biomedical Ethics
Carol Dahl, Ph.D. Biospect, Inc.
Chi Dang, M.D., Ph.D. Professor, Division of Hematology, Johns
Hopkins University Department of Medicine
Alfred G. Gilman, M.D., Ph.D. Regental Professor and Chairman,
Department of Pharmocology, University of Texas Southwestern
Medical Center
Allen S. Lichter, M.D. Newman Family Professor of Radiation
Oncology, Dean, University of Michigan Medical School
Candace Swimmer, Ph.D. Research Fellow, Department of Genome
Biochemistry, Exelixis, Inc.
Shirley M. Tilghman, Ph.D. President, Princeton University
Although the reviewers listed above have provided many construc-

tive comments and suggestions, they were not asked to endorse the con-
clusions or recommendations nor did they see the final draft of the report
before its release. The review of this report was overseen by Enriqueta C.
Bond, Ph.D., President, Burroughs Wellcome Fund and Charles E.
Phelps, Ph.D., Provost University of Rochester. Appointed by the Na-
tional Research Council and Institute of Medicine, they were responsible
for making certain that an independent examination of this report was
carried out in accordance with institutional procedures and that all re-
view comments were carefully considered. Responsibility for the final
content of this report rests entirely with the authoring committee and the
institution.
vi
Acknowledgments
The committee gratefully acknowledges the contributions of many

individuals who provided invaluable information and data for the study,
either through formal presentations or through informal contacts with the
study staff:
Herman Alvarado, Bi Ade, Lee Babiss, Wendy Baldwin, John Carney,
Robert Cook-Deegan, Carol Dahl, James Deatherage, Joseph DeRisi, Marie
Freire, Jack Gibbons, John Gohagan, Eric Green, Judith Greenberg, Ed-
ward Hackett, Edward Harlow, Nathaniel Heintz, David Hirsh, Nancy
Hopkins, James Jensen, Marvin Kalt, Richard Klausner, William Koster,
Rolph Leming, Joan Leonard, Arnold Levine, David Livingston, Rochelle
Long, David Longfellow, Michael Lorenz, Richard Lyttle, Pamela Marino,
Richard Nelson, Emanuel Petricoin, Michael Rogers, Jacques Rossouw,
Walter Schaefer, William Schraeder, Stuart Schreiber, Edward Scolnick,
Scott Somers, Paula Stephan, Marcus Stoffel, Robert Strausberg, Daniel
Sullivan, Roy Vagelos, Craig Venter, LeRoy Walters, Barbara Weber,
Michael Wigler, Robert Wittes.
vii

Acronyms
AAAS – American Association for the Advancement of Science

AEC – Atomic Energy Commission (forerunner of DOE)
AFCS – Alliance for Cellular Signaling
AIP – American Institute of Physics
AUTM – Association of University Technology Managers
BAA – Broad Agency Announcement
CDC – Centers for Disease Control and Prevention

CEPH – Centre d’Etude du Polymorphisme Humaine
CERN – Conseil European Pour La Rechierche Nucleaire
CES – Cooperative Extension Services
CGAP – Cancer Genome Anatomy Project
COSEPUP – Committee on Science, Engineering, and Public Policy
CRADA – Cooperative Research and Development Agreement
CSR – Center for Scientific Review
DARPA – The Defense Advanced Research Projects Agency

DHHS – Department of Health and Human Services
DOD – Department of Defense
DOE – Department of Energy
DTP – Developmental Therapeutics Program
EDRN – The Early Detection Research Network

EPA – Environmental Protection Agency
EST – Expressed Sequence Tag
ix
x ACRONYMS
FDA – Food and Drug Administration
GPRA – Government Performance and Results Act
HGP – Human Genome Project

HHMI – Howard Hughes Medical Institute
HRT – Hormone Replacement Therapy
HUGO - Human Genome Organization
HUPO – Human Proteome Organization
INS – Immigration and Naturalization Service

IRG – Integrated Review Groups
IUPAP – International Union of Pure and Applied Physics
JCSG – Joint Center for Structure Genomics
MBL – Marine Biology Laboratory

MMHCC – Mouse Models of Human Cancers Consortium
MOU – Memoranda of Understanding
NACA – National Advisory Committee for Aeronautics

NAS – National Academy of Sciences
NASA – National Aeronautics and Space Administration
NCAB – National Cancer Advisory Board
NCI – National Cancer Institute
NDRC – National Defense Research Committee
NHGRI – National Human Genome Research Institute
NHLBI – National Heart Lung and Blood Institute
NIAID – National Institute of Allergy and Infectious Diseases
NIEHS – National Institute of Environmental Health Science
NIGMS – National Institute of General Medical Sciences
NIH – National Institutes of Health
NOAA – National Oceanic and Atmospheric Administration
NOARL – Naval Oceanographic and Atmospheric Research Laboratory
NRAC – Naval Research Advisory Committee
NRC – National Research Council
NRSA – National Research Service Awards
NSF – National Science Foundation
NTP – National Toxicology Program
OES – Office of Experiment Stations

OMB – Office of Management and Budget
ONR – Office of Naval Research

ACRONYMS xi
OSHA – Occupational Safety and Health Administration

OSTP – Office of Science and Technology Policy
OTA – Office of Technology Assessment
OTIR – Office of Technology and Industrial Relations
PA – Program Announcement
PDB – Protein Data Bank
PFGRC – Pathogen Functional Genomics Resource Center
PSAC – Presidents Science Advisory Committee
PSI – Protein Structure Initiative
RAID – Rapid Access to Intervention Development

RFA – Request for Applications
RTLA – Reach Through License Agreements
SBIR – Small Business Innovation Research

SDI – Strategic Defense Initiative
SEP – Special Emphasis Panels
SNP – Single Nucleotide Polymorphisms
SPORE – Specialized Programs of Research Excellence
SSC – Superconducting Super Collider
STC – Science and Technology Centers
STTR – Small Business Technology Transfer
TIGR – The Institute for Genomic Research
UIP – Unconventional Innovations Program

URA – Universities Research Association
USDA – United States Department of Agriculture
VA – Department of Veterans Affairs

VRC – Vaccine Research Center
WHI – Women’s Health Initiative


Contents
EXECUTIVE SUMMARY 1
1 INTRODUCTION 12
The National Cancer Policy Board, 15
2 DEFINING “LARGE-SCALE SCIENCE” IN BIOMEDICAL

RESEARCH 17
Examples of potential large-scale biomedical research
projects, 20
Genomics, 21
Structural Biology and Proteomics, 22
Bioinformatics, 23
Diagnostics and Biomarker Research, 23
Patient Databases and Specimen Banks, 24
Potential obstacles to undertaking large-scale biomedical
research projects, 24
Determining Appropriate Funding Mechanisms and
Allocation of Funds, 24
Organization and Management, 25
Personnel Issues, 26
Information Sharing and Intellectual Property Concerns, 27
Summary, 28
3 MODELS OF LARGE-SCALE SCIENCE 29

The Human Genome Project, 31
Past examples of large-scale projects funded by NCI, 40
Cancer Chemotherapy Program, 41
xiii
xiv CONTENTS
Chemical Carcinogenesis Program, 43

Cancer Virus Program, 44
Recently developed large-scale projects at NCI, 45
The Cancer Genome Anatomy Project, 45
Early Detection Research Network, 47
Unconventional Innovations Program, 48
Mouse Models of Human Cancers Consortium, 50
Specialized Programs of Research Excellence, 52
The Molecular Targets Laboratory, 53
Recent examples from other branches of NIH, 54
NIGMS Glue Grants, 54
NIGMS Protein Structure Initiative, 57
The Pathogen Functional Genomics Resource Center, 61
The Women’s Health Initiative, 62
Vaccine research, 64
National Science Foundation’s Science and Technology
Centers Program, 65
The SNP Consortium, 67
Human Proteome Organization, 70
Howard Hughes Medical Institute, 71
Synchrotron resources at the National Laboratories, 73
Defense Advanced Research Projects Agency, 74
Summary, 77
4 FUNDING FOR LARGE-SCALE SCIENCE 80

History of federal support for scientific research, 82
Allocation of federal funds for scientific research, 83
NIH funding, 94
Congressional Appropriations to NIH, 95
NIH Peer Review of Funding Applications, 105
Funding Mechanisms for Extramural Research and
Solicitation of NIH Grant Applications, 109
Nonfederal funding of large-scale biomedical research
projects, 115
Industry Funding of Large-Scale Biomedical Research, 116
Nonprofit Funding of Large-Scale Biomedical Research, 123
Issues associated with international collaborations, 125
Summary, 126
5 ORGANIZATION AND MANAGEMENT OF LARGE-

SCALE BIOMEDICAL RESEARCH PROJECTS 130
Examples of management assessment for large-scale
projects, 131

CONTENTS xv
Assessment of Federally Funded Laboratories, 131

Evaluation of the National Science Foundation’s Science
and Technology Centers Program, 132
Special considerations for the management of large-scale
biomedical research projects, 133
The industry model of project management: comparison
with academia, 136
Summary, 138
6 TRAINING AND CAREER STRUCTURES IN

BIOMEDICAL RESEARCH 140
The traditional academic training and career structure in
biomedical science, 143
Overview of trends in the bioscience workforce, 148
Ph.D. Scientists, 148
M.D. Scientists, 155
Potential impact of large-scale research on biomedical
training and career structures, 157
Summary, 160
7 INTELLECTUAL PROPERTY AND ACCESS TO

RESEARCH TOOLS AND DATA 162
Nonexclusive and exclusive licensing, 167
Reach-through license agreements, 169
Research exemptions, 170
Patent pools, 172
University policies and technology transfer offices, 174
Examples of intellectual property and data sharing issues
associated with large-scale projects, 176
Genomics and DNA Patents, 176
Protein Patents, 181
Databases, 182
Patient confidentiality and consent, 183
Effects of intellectual property claims on the sharing of
data and research tools, 184
Summary, 190
8 FINDINGS AND RECOMMENDATIONS 192
REFERENCES 202
APPENDIX 213
INDEX 269


Executive Summary
T
he nature of biomedical research has been evolving in recent years.
Relatively small projects initiated by single investigators have tra-
ditionally been and continue to be the mainstay of cancer research,
as well as biomedical research in other fields. Recently, however, techno-
logical advances that make it easier to study the vast complexity of bio-
logical systems have led to the initiation of projects with a larger scale and
scope (Figure ES-1). For instance, a new approach to biological experi-
mentation known as “discovery science” first aims to develop a detailed
inventory of genes, proteins, and metabolites in a particular cell type or
tissue as a key information source. But even that information is not suffi-
cient to understand the cell’s complexity, so the ultimate goal of such
research is to identify and characterize the elaborate networks of gene
and protein interactions in the entire system that contribute to disease.
This concept of systems biology is based on the premise that a disease can
be fully comprehended only when its cause is understood from the mo-
lecular to the organismal level. For example, rather than focusing on single
aberrant genes or pathways, it is essential to understand the comprehen-
sive and complex nature of cancer cells and their interaction with sur-
rounding tissues. In many cases, large-scale analyses in which many pa-
rameters can be studied at once may be the most efficient and effective
way to extract functional information and interactions from such complex
biological systems.
The Human Genome Project is the biggest and best-known large-
scale biomedical research project undertaken to date. Another project of
that size is not likely to be launched in the near future, but many other
Copyright © 2003 National Academy of Sciences. All rights

1 reserved.
2 LARGE-SCALE BIOMEDICAL SCIENCE
Conventional small-scale research → Large-scale → Very large-scale collaborative research

Smaller, more specific goals → Broad goals (encompassing an entire field of
inquiry)
Short-term objectives → Requires long-range strategic planning
Relatively shorter time frame → Often a longer time frame
Lower total cost, higher unit cost → Higher total cost, lower unit cost
Hypothesis driven, undefined deliverables → Problem-directed with well-defined
deliverables and endpoints
Small peer review group approval sufficient → Acceptance by the field as a whole important
Minimal management structure → Larger, more complex management
structure
Minimal oversight by funders → More oversight by funders
Single principal investigator → Multi-investigator and multi-institutional
More dependent on scientists in training → More dependent on technical staff
Generally funded by unsolicited, → Often funded through solicited cooperative
investigator-initiated (R01) grants agreements
More discipline-oriented → Often interdisciplinary
Takes advantage of infrastructure and → Develops scientific research capacity,
technologies generated by large-scale projects infrastructure, and technologies
May or may not involve bioinformatics → Data and outcome analysis highly
dependent on bioinformatics
FIGURE ES-1 The range of attributes that may characterize scientific research.
There is no absolute distinction—indeed there is much overlap—between the
characteristic of small- and large-scale research. Rather, these characteristics vary
along a continuum that extends from traditional independent small-scale projects
through very large, collaborative projects. Any single project may share some
characteristics with either of these extremes.
projects that fall somewhere between the Human Genome Project and the
traditional small projects have already been initiated, and many more
have been contemplated. Indeed, the director of the National Institutes of
Health (NIH) recently presented to his advisory council a “road map” for
the agency’s future that includes a greater emphasis on “revolutionary
methods of research” focused on scientific questions too complex to be
addressed by the single-investigator scientific approach. He noted that
the NIH grant process will need to be adapted to accommodate this new
large-scale approach to scientific investigation, which may conflict with
traditional paradigms for proposing, funding, and managing science
projects that were designed for smaller-scale, hypothesis-driven research.

EXECUTIVE SUMMARY 3
The recent interest in adopting large-scale research methods has gen-

erated many questions, then, as to how such research in the biomedical
sciences should be financed and conducted. Accordingly, the National
Cancer Policy Board determined that a careful examination of these issues
was warranted at this time. The purpose of this study was to (1) define the
concept of “large-scale science” with respect to cancer research; (2) iden-
tify examples of ongoing large-scale projects to determine the current
state of the field; (3) identify obstacles to the implementation of large-
scale projects in biomedical research; and (4) make recommendations for
improving the process for conducting large-scale biomedical science
projects, should such projects be undertaken in the future.
Although the initial intent of this study was to examine large-scale
cancer research, it quickly became clear that issues pertaining to large-
scale science projects have broad implications that cut across all sectors
and fields of biomedical research. Large-scale endeavors in the biomedi-
cal sciences often involve multiple disciplines and contribute to many
fields and specialties. The Human Genome Project is a classic example of
this concept, in that its products can benefit all fields of biology and
biomedicine. The same is likely to be true for many other large-scale
projects now under consideration or underway, such as the Protein Struc-
ture Initiative (PSI) and the International HapMap Project. Furthermore,
given the funding structures of NIH, the launch of a large-scale project in
one field could potentially impact progress as well as funding in other
fields. Thus, while this report emphasizes examples from cancer research
whenever feasible, the committee’s recommendations are generally not
specific to the National Cancer Institute (NCI) or to the field of cancer
research; rather, they are directed toward the biomedical research com-
munity as a whole. Indeed, it is the committee’s belief that all fields of
biomedical research, including cancer research, could benefit from imple-
mentation of the recommendations presented herein.
Ideally, large-scale and small-scale research should complement each
other and work synergistically to advance the field of biomedical research
in the long term. For example, many large-scale projects generate hypoth-
eses that can then be tested in smaller research projects. However, the
new large-scale research opportunities are challenging traditional aca-
demic research structures because the projects are bigger, more costly,
often more technologically sophisticated, and require greater planning
and oversight. These challenges raise the question of how the large-scale
approach to biomedical research could be improved if such projects are to
be undertaken in the future. The committee concluded that such improve-
ment could be achieved by adopting the seven recommendations pre-
sented here to address these issues.
The first three recommendations suggest a number of changes in the

way scientific opportunities for large-scale research are initially assessed

as they emerge from the scientific community, as well as in the way
specific projects are subsequently selected, funded, launched, and evalu-
ated (Table ES-1). Although the procedures of NIH and other federal
agencies have a degree of flexibility that has allowed some large-scale
research endeavors to be undertaken, a mechanism is needed through
which input from innovators in research can be routinely collected and
incorporated into the institutional decisionmaking processes. Also needed
is a more standard mechanism for vetting various proposals for large-
scale projects. For example, none of the large projects initiated by NCI to
date has been evaluated in a systematic manner. There is also a need for
greater planning and oversight by federal sponsors during both the ini-
tiation and phase-out of a large-scale project. Careful assessment of past
and current large-scale projects to identify best practices and determine
whether the large-scale approach adds value to the traditional models
of research would also provide highly useful information for future en-
deavors.
Recommendation 1: NIH and other federal funding agencies that

support large-scale biomedical science (including the National Sci-
ence Foundation [NSF], the U.S. Department of Energy [DOE], the
U.S. Department of Agriculture [USDA], and the U.S. Department
of Defense [DOD]) should develop a more open and systematic
method for assessing important new research opportunities emerg-
ing from the scientific community in which a large-scale approach
is likely to achieve the scientific goals more effectively or efficiently
than traditional research efforts.
• This method should include a mechanism for soliciting and

evaluating proposals from individuals or small groups as well
as from large groups, but in either case, broad consultation
within the relevant scientific community should occur before
funding is made available, perhaps through ad hoc public con-
ferences. Whenever feasible, these discussions should be NIH-
wide and multidisciplinary.
• An NIH-wide, trans-institute panel of experts appointed by the
NIH director would facilitate the vetting process for assessing sci-
entific opportunities that could benefit from a large-scale approach.
• Once the most promising concepts for large-scale research have
been selected by the director’s panel, appropriate guidelines for
peer review of specific project proposals should be established.
These guidelines should be applied by the institutions that oversee
the projects.

EXECUTIVE SUMMARY 5
TABLE ES-1 Summary of the Challenges Associated with Large-Scale

Biomedical Research Projects, and the Committee’s Recommendations
to Overcome These Difficulties
Difficulties Associated with
Large-Scale Projects Potential Paths to Solutions
No systematic method for assessing Develop an NIH-wide mechanism for
large-scale biomedical research soliciting and reviewing proposals for
opportunities exists. large-scale projects, with input from all
relevant sectors of biomedical science.
Carefully planning and orchestrating Clear but flexible plans for entry into
the launch as well as the phase out of a and phase out from projects should be
large-scale project is difficult, but developed before funding is provided.
imperative for its long term success
and efficiency.
There are very few precedents to guide NCI and NIH should commission a
the planning and oversight of large- thorough analysis of their recent large-
scale endeavors in biomedical science. scale initiatives to determine whether
those efforts have been effective and
efficient in meeting their stated goals
and to aid in the planning of future
large-scale projects.
It is difficult to recruit and retain quali- Institutions should develop new ways
fied scientific managers and staff for to recognize and reward scientific col-
large-scale projects. laborations and team-building efforts.
It can be costly and difficult for investi- NIH should provide funding to preserve
gators to maintain reagents produced and distribute reagents and other research
through large-scale projects and to share tools once they have been created.
them with the research community.
Licensing strategies can affect the NIH should examine systematically the
availability of research tools produced impact of licensing strategies and
by and used for large-scale research should promote licensing practices that
projects. facilitate broad access to research tools.
A seamless transition between Consideration should be given to
discovery and clinical application is pursuing projects initiated by academic
lacking. scientists in cooperation with industry
to achieve large-scale research goals.
• Collaborations among institutes could encourage participation by

smaller institutes that may not have the resources to launch their
own large-scale projects.
• NIH should continue to explore alternative funding mechanisms
for large-scale endeavors, perhaps including approaches similar to
those used by NCI’s Unconventional Innovations Program, as well
as funding collaborations with industry and other federal funding
agencies.

• International collaborations should be encouraged, but an ap-

proach for achieving such cooperation should be determined
on a case by case basis.
Recommendation 2: Large-scale research endeavors should have
clear but flexible plans for entry into and phase out from projects
once the stated ends have been achieved.
• It is essential to define the goals of a project clearly and to monitor
and assess its progress regularly against well-defined milestones.
• Carefully planning and orchestrating the launch of a large-scale
project is imperative for its long-term success and efficiency.
• NIH should be very cautious about establishing permanent infra-
structures, such as centers or institutes, to undertake large-scale
projects, in order to avoid the accumulation of additional Institutes
via this mechanism.
• Historically, NIH has not had a good mechanism for phasing out
established research programs, but large-scale projects should not
become institutionalized by default simply because of their size.
• If national centers with short-term missions are to be established, this
should be done with a clear understanding that they are temporary
and are not meant to continue once a project has been completed.
– Leasing space is one way to facilitate downsizing upon comple-
tion of a project.
– Phase-out funding could enable investigators to downsize over
a period of 2–3 years.
Recommendation 3: NCI and NIH, as well as other federal funding
agencies that support large-scale biomedical science, should com-
mission a thorough analysis of their recent large-scale initiatives
once they are well established to determine whether those efforts
have been effective and efficient in achieving their stated goals and
to aid in the planning of future large-scale projects.
• NIH should develop a set of metrics for assessing the technical
and scientific output (such as data and research tools) of large-
scale projects. The assessment should include an evaluation of
whether the field has benefited from such a project in terms of
increased speed of discoveries and their application or a reduc-
tion in costs.
• The assessment should be undertaken by external, independent
peer review panels with relevant expertise that include academic,
government, and industry scientists.
• To help guide future large-scale projects, the assessment should
pay particular attention to a project’s management and organiza-

EXECUTIVE SUMMARY 7
tional structure, including how scientific and program managers

and staff were selected, trained, and retained and how well they
performed.
• The assessment should include tracking of any trainees involved in
a project (graduate students and postdoctoral scientists) to deter-
mine the value of the training environment and the impact on
career trajectories.
• The assessment should examine the impact of industry contracts or
collaborations within large-scale research projects. Industry has
many potential strengths to offer such projects, including efficiency
and effective project management and staffing, but intellectual
property issues represent a potential barrier to such collaborations.
Thus, some balance must be sought between providing incentives
for producing the data and facilitating the research community’s
access to the resultant data.
– In pursuing large-scale projects with industry, NIH should care-
fully consider the data dissemination goals of the endeavor be-
fore making the funds available.
– To the extent appropriate, NIH should mandate timely and un-
restricted release of data within the terms of the grant or con-
tract, in the same spirit as the Bermuda rules adopted for the
release of data in the Human Genome Project.
The committee has formulated four additional recommendations

aimed at improving the conduct of possible future large-scale projects.
These recommendations emerged from the committee’s identification of
various potential obstacles to conducting a large-scale research project
successfully and efficiently. To begin with, human resources are key to
the success of any large-scale project. If large-scale projects are deemed
worthy of substantial sums of federal support, they also clearly warrant
the highest-caliber staff to perform and oversee the work. But if qualified
individuals, especially at the doctoral level, are expected to participate in
such undertakings, they must have sufficient incentives to take on the
risks and responsibilities involved. In particular, effective administrative
management and committed scientific leadership are crucial for meeting
expected milestones on schedule and within budget; thus the success of a
large-scale project is greatly dependent upon the skills and knowledge of
the scientists and administrators who manage it, including those within
the federal funding agencies. However, it may be quite difficult to recruit
staff with the skills to meet this need because of the unusual status of such
managerial positions within the scientific career structure, and because
scientists rarely undergo formal training in management. Young investi-
gators and trainees also need recognition for their efforts that contribute

to elaborate, long-term, and large multi-institutional efforts. Thus, the

committee concluded that both universities and government agencies
need to develop new approaches for assessing teamwork and manage-
ment, as well as novel ways of recognizing and rewarding accomplish-
ment in such positions.
Recommendation 4: Institutions should develop the necessary in-
centives for recruiting and retaining qualified scientific managers
and staff for large-scale projects, and for recognizing and reward-
ing scientific collaborations and team-building efforts.
• Funding agencies should develop appropriate career paths for indi-

viduals who serve as program managers for the large-scale projects
they fund.
• Academic institutions should develop appropriate career paths,
including suitable criteria for performance evaluation and promo-
tion, for those individuals who manage and staff large-scale col-
laborative projects carried out under their purview.
• Industry and The National Laboratories may both serve as in-
structive models in achieving these goals, as they have a history
of rewarding scientists for their participation in team-oriented
research.
• It is important to establish guiding principles for such issues as
equitable pay and benefits, job stability, and potential for advance-
ment to avoid relegating these valuable scientists and managers to
a “second-tier” status. Federal agencies should provide adequate
funding to universities engaged in large-scale biomedical research
projects so that these individuals can be sufficiently compensated
for their role and contribution.
• Universities, especially those engaged in large-scale research,
should develop training programs for scientists involved in such
projects. Examples include courses dealing with such topics as
managing teams of people and working toward milestones within
timelines. Input from industry experts who deal routinely with
these issues would be highly valuable.
The committee also identified potential impediments to deriving the

greatest benefits from the products of large-scale endeavors in terms of
scientific progress for biomedical research in general. Large-scale projects
are most likely to speed the progress of biomedical research as a whole
when their products are made widely available to the broad scientific
community. However, concerns have been raised in recent years about
the willingness and ability of scientists and their institutions to share
data, reagents, and other tools derived from their research. Since a pri-

EXECUTIVE SUMMARY 9
mary goal of many large-scale biomedical research projects is to produce

data and research tools, NIH should facilitate the sharing of data and the
distribution of reagents to the extent feasible. Currently, NIH grants gen-
erally do not provide funds for this purpose, making it difficult for inves-
tigators to maintain reagents and share them with the research commu-
nity. This obstacle could be reduced if NIH provided such funds for
large-scale research projects.
Recommendation 5: NIH should draft contracts with industry to
preserve reagents and other research tools and distribute them to
the scientific community once they have been produced through
large-scale projects.
• The Pathogen Functional Genomics Resource Center, established
through a contract with the National Institute of Allergy and Infec-
tious Diseases, could serve as a model for this undertaking.
• The distribution of standardized and quality-controlled reagents
and tools would improve the quality of the data obtained through
research and make it easier to compare data from different investi-
gators.
• Producing the reagents and making them widely available to many
researchers would be more cost-effective than providing funds to a
few scientists to produce their own.
An issue closely related to the sharing of data and reagents is the
licensing of intellectual property. Many concerns have been raised in re-
cent years about the challenges and expenses associated with the transfer
of patented technology from one organization to another. Innovations
that can be used as research tools may offer the greatest challenge in this
regard because it is difficult to predict the future applications and value
of a particular tool, and because a number of different tools may be needed
for a single research project. Since many large-scale projects in the bio-
sciences aim to produce data and other tools for future research, this
subject is especially salient for large-scale research. The committee con-
cluded that NIH should continue to promote the broad accessibility of
research tools derived from federally funded large-scale research to the
extent feasible, while at the same time considering the appropriate role
for intellectual property rights in a given project. However, in the absence
of adequate information and scholarly assessment, it is difficult to deter-
mine how NIH could best accomplish that goal. Thus, the committee
recommends that such an assessment be undertaken, and that appropri-
ate actions be taken based on the findings of the study.
Recommendation 6: NIH should commission a study to examine
systematically the ways in which licensing practices affect the avail-

ability of research tools produced by and used for large-scale bio-

medical research projects.
• Whenever possible, NIH and NCI should use their leverage and
resources to promote the free and open exchange of scientific
knowledge and information, and to help minimize the time and
expense of technology transfer.
• Depending on the findings of the proposed study, NIH should
promote licensing practices that facilitate broad access to research
tools by issuing licensing guidelines for NIH-funded discoveries.
In addition to the role of federal funding agencies, the committee
considered the role of industry and philanthropies in conducting large-
scale biomedical research. Public–private collaborations provide a way to
share the costs and risks of innovative research, as well as the benefits.
Philanthropies and other nonprofit organizations can play an important
role in launching nontraditional projects that do not fit well with federal
funding mechanisms. Pharmaceutical and biotechnology companies also
make enormous contributions to biomedical research worldwide. Tradi-
tionally, the role of independent companies has been to pursue applied
research aimed at producing an end product; however, the distinction
between “applied” and “basic” research has blurred in recent years, in
part because of novel approaches used for drug discovery and develop-
ment. A recent focus by academic scientists on translational research,
which aims to translate fundamental discoveries into clinically useful
practices, has further obscured the distinction.
Several recent projects initiated and funded by industry or carried
out in cooperation with industry and nonprofit organizations clearly
demonstrate the potential value of contributions by these entities to
large-scale research endeavors. The Single Nucleotide Polymorphism,
or SNP, consortium is a prime example of how effective these sectors
can be when involved in a large-scale research projects. Industry in
particular has many inherent strengths that could be brought to bear on
large-scale biomedical research efforts, such as experience in coordinat-
ing and managing teams of scientists working toward a common goal.
Combining the respective strengths of academia and industry could
optimize the pace of biomedical research and development, potentially
leading to more rapid improvements in human health. Thus, the com-
mittee recommends that cooperation between academia and industry be
encouraged for large-scale research projects whenever feasible.
Recommendation 7: Given the changing nature of biomedical re-
search, consideration should be given to pursuing projects initiated
by academic scientists in cooperation with industry to achieve the

EXECUTIVE SUMMARY 11
goals of large-scale research. When feasible, such cooperative ef-

forts could entail collaborative projects, as well as direct funding of
academic research by industry, if the goals of the research are mutu-
ally beneficial.
• Academia is generally best suited for making scientific discoveries,
while the strength of industry most often lies in its ability to de-
velop or add value to these discoveries.
• Establishing a more seamless connection between the two endeav-
ors could greatly facilitate translational research and thus speed
clinical applications of new discoveries.
Great strides in biomedical research have been made in recent de-
cades, due largely to a robust investigator-initiated research enterprise.
Recent technological advances have provided new opportunities to fur-
ther accelerate the pace of discovery through large-scale research initia-
tives that can provide valuable information and tools to facilitate this
traditional approach to experimentation. Recent large-scale collaborations
have also allowed scientists to tackle complex research questions that
could not readily be addressed by a single investigator or institution. The
current leadership of NIH and many scientists in the field clearly have
expressed an interest in integrating the discovery approach to biomedical
science with hypothesis-driven experimentation. As a result, at least some
large-scale endeavors in the biomedical sciences are likely to be under-
taken in the future as well. But because the large-scale approach is rela-
tively new to the life sciences, there are few precedents to follow or learn
from when planning and launching a new large-scale project. Moreover,
there has been little formal or scholarly assessment of large-scale projects
already undertaken.
Now is the time to address the critical issues identified in this report
in order to optimize future investments in large-scale endeavors, what-
ever they may be. The ultimate goal of biomedical research, both large-
and small-scale, is to advance knowledge and provide society with useful
innovations. Determining the best and most efficient method for accom-
plishing that goal, however, is a continuing and evolving challenge. Fol-
lowing the recommendations presented here could facilitate a move to-
ward a more open, inclusive, and accountable approach to large-scale
biomedical research, and help strike the appropriate balance between
large- and small-scale research to maximize progress in understanding
and controlling human disease.

Introduction
H
istorically, most cancer research has been conducted through
small independent projects initiated by individual investigators
with relatively small research groups. Such research is driven
by focused hypotheses addressing specific biological questions. There will
always be a need for this traditional approach to research; in recent years,
however, it has also become more feasible to undertake projects on a
broader and larger scale, thereby developing extensive pools of data and
research tools that can facilitate those more conventional efforts. Large-
scale science projects, in which many investigators often work to-
ward a common goal, have become quite common, and perhaps even the
norm in some fields of scientific research, such as high-energy physics
(Galison and Hevly, 1992; Heilbron and Kevles, 1988). The large-scale
approach has also been used for decades or even centuries to develop
astronomical charts and geological and oceanic maps that can be used as
tools for scientific inquiry (see Appendix). However, the concept is still
relatively new in the biomedical sciences, including cancer research.
This new paradigm of biomedical research has become possible in
part through technological advances that allow for high-throughput data
collection and analysis—an approach referred to as “discovery science.”
Traditional biomedical research is conducted by small groups that test
hypotheses and are interactive but not highly collaborative, whereas large-
scale biology often involves large, highly collaborative groups that deal
with the high-throughput collection and analysis of large bodies of data.
The two approaches can be synergistic in the long term when large-scale

12 reserved.
INTRODUCTION 13
projects produce data that can be used to generate hypotheses, which can
then be tested with smaller-scale experiments.
The biggest and most visible large-scale research project conducted in
biology to date is the Human Genome Project (HGP), aimed at mapping
and sequencing the human genome. While not exclusive to the study of
cancer, the products of this project can serve as research tools for the
study of cancer, and thus will have a far-reaching influence on the pro-
gress and direction of cancer research in the future. As a result, there is
considerable interest in the field of cancer research in developing other
similar projects with broad potential benefits. Projects of the scope and
scale of the HGP are perhaps unlikely to be launched in the foreseeable
future, but many projects that are larger or broader in scope than tradi-
tional efforts are already under way. One such initiative in cancer re-
search is the Cancer Genome Anatomy Project (CGAP) of the National
Cancer Institute.1 The goal of this project is to develop gene expression
profiles of normal, precancerous, and cancerous cells, which could then
be used by many investigators to search for new methods of cancer detec-
tion, diagnosis, and treatment.
At the same time, this recent interest in large-scale biomedical science
projects raises many questions regarding how such projects should be
evaluated, funded, initiated, organized, managed, and staffed. Once it
has been decided that a large-scale approach is appropriate for achieving
a specific goal, a variety of issues—such as staffing and scientific training;
challenges in communication, data sharing, and decision making; and
intellectual property issues (patenting, licensing, and trade secrets)—must
be considered in choosing the appropriate venue for the research. Diffi-
culties can also arise because research within large-scale projects may be
conducted by multiple institutions and is often multidisciplinary, thus
requiring management of diverse complementary components. In addi-
tion, such projects often require strategic planning with clearly defined
endpoints and deliverables, they often entail technology development,
and they generally have longer timeframes than conventional research.
These characteristics may not mesh well with the traditional organization
and operation of research institutions, especially with respect to funding
mechanisms and peer review, ownership of intellectual property, scien-
tific training, career advancement, and planning and management over-
sight within academic institutions.
Many decisions must be made before a large-scale project is launched,
such as where the funding will come from and how it will be made avail-
able to investigators; what projects and institutions will be funded; and
how activities will be organized, managed, completed, and evaluated.
1 See <http://cgap.nci.nih.gov/>.

The National Institutes of Health (NIH), in contrast to some other fed-

eral agencies, has not developed a standardized or institutionalized ap-
proach for making decisions about large-scale science projects, which
require a long-term funding commitment. For very large projects that
involve multiple federal agencies, there is also a need to coordinate
funding. Moreover, such projects often attract international coopera-
tion, so mechanisms for addressing such cooperation need to be in place.
Finally, because large-scale science is very expensive, there is always
concern that it will reduce the pool of money available for smaller, tradi-
tionally funded projects and thereby slow the progress of innovation.
As noted above, however, there should ideally be a long-term synergy
between large- and small-scale projects in biomedical science, with the
former providing new research tools and resources for the advancement
of the latter.
A variety of models exist for carrying out large-scale biological re-
search projects, and each has its strengths and advantages. As noted ear-
lier, the Human Genome Project is the largest and most visible undertak-
ing in biology to date. In the United States, public funding for the project
came from both NIH and the U.S. Department of Energy (DOE), but only
after considerable debate over the merit of the project, the best way to
accomplish its goals, and how to fund it adequately without reducing
support for other aspects of biomedical research. In the end, significant
investment was also made by private industry. With the successful com-
pletion of the draft sequence (Lander et al., 2001; Venter et al., 2001), the
project is now being hailed as a remarkable example of what can be ac-
complished through a large-scale science venture in biology. But is this
the best or only way to take on future large-scale biomedical research?
There are other strategies for funding and organizing such projects, some
of which have never been used in biology but have worked well in other
scientific fields.
Because the concept of large-scale science is relatively new to the field
of biomedical research, and there is increasing interest is using this re-
search format to advance the study of cancer, the National Cancer Policy
Board determined that it would be useful at this time to address some of
the issues and questions outlined above. The purpose of the study docu-
mented in this report, then, was to:
• Define the concept of large-scale biomedical science, with a par-

ticular focus on its application to cancer research.
• Examine the current state of large-scale science in biomedical re-
search (what is being done and how).
• Examine other potential models of large-scale biomedical research.

INTRODUCTION 15
The National Cancer Policy Board
The National Cancer Policy Board was established in 1997 within the Institute of
Medicine and the National Research Council to address broad policy issues that
affect cancer research and care in the United States, and to recommend ways of
advancing the nation’s effort to combat the disease. The board, consisting of mem-
bers drawn from outside the federal government, includes health care consumers,
providers, and researchers in a variety of disciplines in the sciences and humanities.
The board meets at least three times per year to review progress; discuss emerg-
ing issues; and gather information and views from representatives of the private and
public sectors, including many federal and state agencies that sponsor or conduct
related work. The board analyzes information; issues reports and recommendations,
prepared under its direction by professional staff members; and may commission
papers and hold workshops in support of those projects. It also oversees reports
prepared by committees appointed to conduct a specific task.
• Examine the ways in which the field of biomedical research is

adapting to the inclusion of large-scale projects.
• Identify obstacles to the implementation of large-scale projects in
cancer research.
• Provide policy recommendations for improving the process for
conducting large-scale projects in cancer research should they be under-
taken in the future.
This report is organized as follows.
Chapter 2 develops a working definition of “large-scale biomedical
research” within the framework of this report. It also provides brief ex-
amples of the types of projects that may be amenable to the large-scale
research approach, as well as a brief overview of the challenges and im-
pediments involved in using this approach.
Chapter 3 provides in-depth information about a wide variety of past
and current large-scale research models or strategies undertaken by the Na-
tional Cancer Institute (NCI) and other branches of NIH, as well as examples
from outside of NIH, including both public and private endeavors.
Chapter 4 presents an overview of the available funding sources and
mechanisms for scientific research, with emphasis on how they are adapt-
ing to the emergence of large-scale projects in the biomedical sciences.
Chapter 5 reviews the role of project management, oversight, and
assessment in large-scale research endeavors.
Chapter 6 provides a general overview of trends in the training and
career development of biomedical scientists, and includes a discussion of
how large-scale projects may influence or be affected by these trends.

Chapter 7 examines the role of intellectual property in biomedical

research, with particular emphasis on the availability of large-scale data
and research tools.
Chapter 8 summarizes the key findings of the study and presents the
committee’s recommendations.

Defining “Large-Scale Science”

in Biomedical Research
T
he term “large-scale science” is defined and used in many differ-
ent ways (National Research Council, 1994). The concept can vary
greatly across fields and disciplines, or even across funding agen-
cies; what is “large” for biology, for example, may be quite modest for
space science or high-energy physics. Similarly, a large project in cancer
research may pale in comparison with the Human Genome Project. The
concept may also vary over time, in part as a result of technological ad-
vances. For instance, because of enormous advances in DNA sequencing
technology, the time and cost of sequencing a mammalian genome are
now considerably lower than was the case when the Human Genome
Project (HGP) was launched; thus such projects are becoming less likely
to be viewed as exceptional, large-scale undertakings.
Unfortunately, the concepts of “large” and “small” science are often
stereotyped in discussions of relative merit. Yet inaccurate generaliza-
tions belie the complexity of the terms. It is therefore essential to define
clearly what is and is not meant by large-scale science within the context
of this study. For the purposes of this report, a project may be character-
ized as large-scale if it serves any or all of the following three objectives:
• Creation of large-scale products (e.g., generating masses of related

data to accomplish a single broad mission or goal)
• Developing large-scale infrastructure (e.g., generating databases
and bioinformatics tools, or advancing the speed and volume of research
through improved instrumentation)

17 reserved.
• Addressing large and complex but focused problems that have a

broad impact on biomedical or cancer research and may require interac-
tions or collaborations among multiple investigators and institutions
Biomedical research projects are not easily classified as either small-

or large-scale because there is considerable overlap among the attributes
that could be used to define them. Each attribute can be characterized
along a continuum from what is typical for conventional small-scale re-
search to what is typical for a very large-scale, collaborative endeavor (see
Figure 2-1). Any given project may have a combination of attributes that
fall on different points along this continuum. Large-scale projects tend
to be very resource intensive (where the term “resource” may include
Conventional small-scale research → Large-scale → Very large-scale collaborative research

Smaller, more specific goals → Broad goals (encompassing an entire field of
inquiry)
Short-term objectives → Requires long-range strategic planning
Relatively shorter time frame → Often a longer time frame
Lower total cost, higher unit cost → Higher total cost, lower unit cost
Hypothesis driven, undefined deliverables → Problem-directed with well-defined
deliverables and endpoints
Small peer review group approval sufficient → Acceptance by the field as a whole important
Minimal management structure → Larger, more complex management
structure
Minimal oversight by funders → More oversight by funders
Single principal investigator → Multi-investigator and multi-institutional
More dependent on scientists in training → More dependent on technical staff
Generally funded by unsolicited, → Often funded through solicited cooperative
investigator-initiated (R01) grants agreements
More discipline-oriented → Often interdisciplinary
Takes advantage of infrastructure and → Develops scientific research capacity,
technologies generated by large-scale projects infrastructure, and technologies
May or may not involve bioinformatics → Data and outcome analysis highly
dependent on bioinformatics
FIGURE 2-1 The range of attributes that may characterize scientific research.
There is no absolute distinction—indeed there is much overlap—between the
characteristic of small- and large-scale research. Rather, these characteristics vary
along a continuum that extends from traditional independent small-scale projects
through very large, collaborative projects. Any single project may share some
characteristics with either of these extremes.

DEFINING “LARGE-SCALE SCIENCE” IN BIOMEDICAL RESEARCH 19
money, space and equipment, and personnel); thus they require collective
agreement or buy-in from the larger scientific community, rather than just
a small number of experts in a subspecialty. To achieve such agreement,
large-scale projects must be mission or goal oriented, with clearly defined
endpoints and deliverables that create infrastructure or scientific capacity
to enhance future research endeavors. Such infrastructure may include
products such as databases and new technologies that could be used as
research tools by a significant portion of the scientific community and
would provide a common platform for research. In other words, a major
intent of such projects is to enable the progress of smaller projects. Tech-
nological advances have created a need for data-rich foundations for many
cutting-edge research proposals that are investigator initiated and hy-
pothesis driven. Thus, many large-scale projects can be thought of as
inductive or generating hypotheses, as opposed to deductive or testing
hypotheses, the latter being more commonly the realm of smaller-scale
research. Large-scale collaborative projects may also complement smaller
projects by achieving an important, complex goal that could not be ac-
complished through the traditional model of single-investigator, small-
scale research. In either case, the objective of a large-scale project should
be to produce a public good—an end product that is valuable for society
and is useful to many or all investigators in the field.
Unlike traditional investigator-initiated projects, research within
large-scale projects may be conducted by many investigators at multiple
institutions or sometimes even in numerous countries. Such research is
also often multidisciplinary in nature. Thus, the work may require exter-
nal coordination and management of various complementary compo-
nents. It can also be very challenging to analyze the resultant masses of
data and to evaluate the outcomes and scientific capacity of such collabo-
rative research. Furthermore, these unconventional projects have larger
budgets than most projects undertaken in the biomedical sciences, so it
can be difficult to launch them using the traditional NIH funding mecha-
nisms. In principle, however, the unit cost of collecting data in a large-
scale project should be lower. These projects also often have a longer time
frame than smaller projects, and thus require more strategic planning
with intermediate goals and endpoints, as well as a phase-out strategy.
Within the context of this report, the definition of large-scale bio-
medical science does not include exceptionally large laboratories that are
headed by a single principal investigator who is simply funded by mul-
tiple grants obtained through conventional funding sources. Nor does it
include traditional program (P0-1) grants, in which multiple investigators
are provided funding for independent but somewhat related small-scale
projects. Unlike some other fields, large-scale biomedical science usually
does not entail very large research facilities, such as the Fermi National

Accelerator Laboratory for research in high-energy physics. In addition,

large-scale biomedical science is not defined by whether it is basic, trans-
lational, or clinical research, but could entail any of these categories. For
example, cancer clinical cooperative groups may be seen as a form of
clinical large-scale science. The NCI, unlike other NIH Institutes, has set
aside a sum of money to support a large infrastructure to carry out clinical
studies.
Ultimately, the distinction between small- and large-scale biomedical
science is determined by the needs and difficulties entailed in achieving a
given research goal, and by the current capabilities in a particular field.
For example, many traditional investigator-initiated projects in biomedi-
cal research focus on improving our understanding of genes or proteins
that are thought to be of biological interest. In contrast, unconventional
large-scale projects take advantage of economies of scale to produce rela-
tively standardized data on entire classes or categories of biological ques-
tions. Thus, as noted earlier, they may reveal novel areas of research for
follow-up by smaller science projects, and they also provide essential
tools and databases for subsequent research. Large-scale projects may be
the most suitable approach for biological questions that can be addressed
more effectively or efficiently by coordinating the work of many scientists
to produce clearly defined deliverables through the development and use
of advanced technology. Smaller projects are more suitable for address-
ing specific, hypothesis-driven scientific questions, which are essential for
the steady progress and evolution of the field. Such projects are under-
taken by many individual investigators, and often yield unexpected find-
ings that can dramatically alter the course of future research.
Ideally, as noted in Chapter 1, there should be a synergism between
large- and small-scale science in the long term. For example, one of the
frequently cited benefits of the Human Genome Project (HGP) is that it
could facilitate faster, less costly, and easier location and identification of
genes that promote disease when mutated—a goal of many smaller con-
ventional science projects. Both large and small science endeavors can
make important contributions to a particular field, and the appropriate
balance between the two may vary over time. Moreover, because bio-
medical research in general is becoming increasingly interdisciplinary
and technology driven, there may be greater opportunities to reap the
benefits of large-scale projects.
EXAMPLES OF POTENTIAL LARGE-SCALE BIOMEDICAL

RESEARCH PROJECTS
Although the number and variety of potential large-scale biomedical
research projects are probably limitless, there are several areas that have

been widely discussed and may be more feasible now or in the near
future. In fact, a number of such projects are already under way with
support from a variety of sources, including industry, government, and
nonprofit organizations. Several examples of potential projects in four
areas—genomics, structural biology and proteomics, bioinformatics, and
diagnostics and biomarker research—are discussed briefly here as a means
of elaborating on the working definition of large-scale biomedical science
used for this report. Some of these examples are discussed in greater
detail in Chapter 3 as models for conducting large-scale bioscience
research.
Large-scale biomedical research differs from many large-scale under-
takings in the physical sciences in the sense that partial completion or
partial success of a project to collect large pools of biological data would
still be useful. As a result, it may be less risky to undertake a long-range,
large-scale project in the biosciences when future budgets are in question.
For example, production of a partial rather than a comprehensive catalog
of protein structures could still be quite useful to the scientific commu-
nity. In contrast, the building of a large-scale facility, such as a super-
conducting super collider or the Fermi Laboratory is useful only if the
facility were completed and then used successfully by members of the
scientific community to generate data. Likewise, the Manhattan Project to
develop the atomic bomb would have been deemed a failure if only par-
tial progress had been made in attaining the ultimate goal.
Genomics
Thousands of people are now working in genomics—a field that did
not exist 15 years ago. (For a recent summary of genomics funding, see
Figure 4-3 in Chapter 4). The completion of the draft sequence of the
human genome is a tremendous achievement, but a great deal of addi-
tional work is needed to realize the full value of this accomplishment.
DNA sequences provide only limited information about a species. Many
additional layers of information, regulation, and interaction must be deci-
phered if we are to truly understand the workings of the human body in
health and disease. Of the many types of biological information, DNA
sequences are among the easiest to obtain but the most difficult to inter-
pret—that is, they provide minimal information regarding structure and
function. Thus, the sequence of the human genome in itself does not
reveal the “secret of life,” but it is an important tool for answering many
questions in biomedical research.
For example, defining and characterizing the many regulatory ele-
ments in DNA will improve our understanding of how, when, and why
various gene products are generated in both health and disease. The avail-

ability of genome databases should facilitate the development of “whole

genome” screens that can be used to assess the expression of all genes in
a given sample or to examine the resulting phenotypes when the genome
is systematically altered to over- or underexpress the genes. There is also
great interest in defining variation among humans with regard to genetic
polymorphisms in disease-related genes and disease modifier genes—
small differences in the DNA sequence of individuals that may not be
directly responsible for disease per se, but may lead to subtle differences
in susceptibility for various diseases, including cancer, or may contribute
to the variability in response to therapies. Polymorphisms can also serve
as markers for locating genes that do directly contribute to disease when
mutated.
Other examples of genomics-related projects include generating data-
bases of full-length cDNAs—DNA sequences that are complementary to
messenger RNAs, which actually code for proteins, and thus have inter-
vening “intron” sequences removed. These resources could then be used
as tools to study gene expression and function. This is one of the aims of
NCI’s Cancer Genome Anatomy Project (CGAP). There is also great inter-
est in sequencing the genomes of organisms that serve as experimental or
comparative models for biomedical research.
Structural Biology and Proteomics

Structural biology is the study of protein composition and configura-
tion (Burley, 2000). The term “proteomics” refers to the study of the struc-
ture and function of the “proteome”—that is, all proteins produced by the
genome. The expressed products of a given genome can vary greatly across
cell and tissue types, and over time, within the same cell. There are many
opportunities for biochemical modification, regulation, and translocation
between the time when transcription of the DNA into RNA is initiated and
when the final protein product is removed or eliminated from the cells.
Furthermore, proteins do not work alone, but within multisubunit struc-
tures and complex networks; thus there is an immensely sophisticated com-
binatorial complexity to deal with in trying to understand cellular or
organismal function. The pathobiology of disease adds further layers of
complexity that can be quite species-specific. In the case of cancer, for ex-
ample, a great variety of mutations can be found that affect the structure,
interactions, and function of proteins that play key roles in the regulation of
cell growth and survival. Furthermore, the specific mutations present can
vary greatly across different types of cancer, among individual patients,
and even within different tissue layers and cells of a single tumor.
Analogies have been drawn between the HGP and the study of pro-
teomics, but one major difference is the lack of a single objective with a clear

endpoint. In the case of the HGP, the goal was simply to obtain a reference
sequence for each of the chromosomes in a human cell. Because there is no
single “human proteome,” the endpoint will vary depending on what ques-
tion is being addressed. In the case of cancer, for example, there could be
great value in cataloging and studying the unique proteomes of cancer
cells. Novel forms of proteins, altered interactions among proteins, and
altered responses to normal regulation may be discovered.
Bioinformatics
In many aspects, biology is becoming an information science: many
important questions in biology are now being addressed, at least in part,
through interactions with computer science and applied mathematics.
Scientists can now produce immense datasets that allow them to look at
biological information in ways never before possible. For example, it is
now theoretically possible to study complex and dynamic biological sys-
tems quantitatively (Lake and Hood, 2001). Once a large resource of bio-
logical data or information becomes available, however, it becomes a chal-
lenge to use that resource effectively. The new field of bioinformatics
aims to develop the computational tools and protocols needed for estab-
lishing, maintaining, using, and analyzing large sets of data or biological
information. Thus, bioinformatics may constitute one key component of a
large-scale research project aimed at generating large datasets that en-
compass an entire field of inquiry. In cancer research, for example, it
would be useful to catalog and characterize the key molecular changes
cells undergo in the transition from a normal to a neoplastic and meta-
static cell. The development of bioinformatics tools and resources could
also potentially serve as a large-scale research project in itself, because the
availability of standardized bioinformatics tools could lead to greater
uniformity and use of data generated within smaller, more traditional
science projects. There is a great need for a common language and plat-
form for many applications.
Diagnostics and Biomarker Research

Much effort has been devoted to identifying and characterizing “mo-
lecular biomarkers” of cancer—any change at the biochemical or molecu-
lar level that may provide insight into how a particular cancer will be-
have, how it should be treated, and how it is responding to treatment.
There is also great interest in using biomarkers for early detection, since
some cancerous changes may be detectable by molecular methods before
the cells have had a chance to grow into a tumor that can be detected by
physical methods (usually imaging or palpation). For example, cancer

cells can secrete abnormal proteins that might be detected by a blood test.
Many potential markers have been studied over the years, but only a very
few have proven to be clinically useful. However, recent advances in
high-throughput technologies (such as those developed for genomics,
proteomics, and bioinformatics) may make it easier to systematically
search for and assess biomarker candidates.
Patient Databases and Specimen Banks

Collections of archived patient information—including clinical data,
family history, and risk factors, as well as patient samples, such as tissue,
blood, and urine—can be very useful for studying the genetics, biology,
etiology, and epidemiology of diseases, especially when they are linked.
Such collections of information can also be used to examine the long-term
effects of medical interventions. Once established, these annotated data
and specimen banks can be used to address new questions and hypoth-
eses as they arise. Some of the challenges involved in developing this sort
of research tool, in addition to the high cost, include concerns about scien-
tists’ access to the resource, as well as patient confidentiality and informed
consent for future studies. Changing technology can also render older
samples obsolete if the newer methods of analysis require a different
method of sample preservation.
POTENTIAL OBSTACLES TO UNDERTAKING LARGE-SCALE

BIOMEDICAL RESEARCH PROJECTS
Because large-scale science projects may not fit readily into the tradi-
tional molds for biomedical research, there are many factors to consider
and obstacles to overcome in making decisions about whether and how to
conduct such projects in cancer research. A brief overview of these topics
is provided here to elaborate the working definition of large-scale science
in cancer research. Each topic is covered in greater detail in Chapters 4
through 7.
Determining Appropriate Funding Mechanisms and

Allocation of Funds
Buy-in by the leaders of the scientific community as a whole is impor-
tant for the initiation of a large-scale research project, as this mode of
operation is a relatively new concept in biology and has been met with
resistance in the past. There should be some consensus that a large-scale
approach to a scientific problem will add value, and will achieve a given
goal more rapidly, more efficiently, or more completely than would be

possible through conventional funding mechanisms. In other words, it

should be clear that to forego a large-scale approach would result in a lost
opportunity to achieve a certain goal, or significant delays and increased
cost in the long run.
Once a large-scale science project has been agreed upon, funding
sources must be identified. The number and variety of potential funding
sources for biomedical research have increased greatly in the last 50 years.
Sources include several government agencies, many private industries,
and nonprofit organizations, each with a different culture, objectives, and
traditions that may cause it to react quite differently to a given idea for a
large-scale project. For example, industry can be expected to take a greater
interest in projects that appear to offer potential near-term profits, whereas
federal agencies are more likely to fund the generation of basic informa-
tion that could be used as a research tool. However, these distinctions are
rarely clear-cut in biology, and thus there is often overlapping interest
and even competition among potential sponsors of large-scale research
projects. In any case, the decision to offer funding and allocation of the
funds are prerequisites for any large and complex project, as the tradi-
tional funding mechanisms in biomedical research were not designed for
such endeavors.
Once funds have been designated for a large-scale biomedical re-
search project, criteria must be established for determining which indi-
viduals, groups, or institutions will be awarded funds for specific compo-
nents of the project. The vetting process for large-scale projects may
require a different set of questions for evaluating the relative merits of
applicants than those commonly raised for smaller projects. In some cases,
more long-term planning than is typical of traditionally funded projects
might be required to define the objectives, feasibility, and expected prod-
ucts of a large-scale project, including intermediate endpoints for measur-
ing progress and assessing accountability. Such long-range planning is
very challenging in a rapidly changing scientific field, and may be some-
what at odds with the nature of scientific exploration and discovery.
Organization and Management

There is no single formula for organizing and managing a large-scale
research project. The approach can vary greatly depending on the goal
and the methods chosen to achieve it. Nonetheless, it can be said that the
organizational requirements of large-scale science projects are likely to be
quite different from those of the more traditional academic approach to
biomedical science. For large-scale projects, the work may need to be
coordinated among multiple public and private research institutions, or

across disciplines, funding agencies, and even national governments in

the case of international projects.
The typical U.S. academic research laboratory is headed by a single
principal investigator, who oversees the work of more-junior scientists—
such as graduate students and postdoctoral fellows—as well as techni-
cians. There tends to be relatively little hierarchical management of
projects within such laboratories, and little or no management from exter-
nal sources. Because the junior scientists are generally in training to be-
come independent researchers, they should ideally spend much of their
time learning techniques and developing their own independent lines of
research.
Large-scale science projects, in contrast, often require external man-
agement and oversight to some degree so that the work of the participat-
ing groups can be coordinated and kept on track for meeting the program
goals. Once a large-scale project has been launched, it is imperative to
monitor and evaluate its progress against expected milestones, and to
alter course if necessary. When a project requires a multidisciplinary ap-
proach, the potential problems of organization, management, and over-
sight are even greater because of difficulties in communicating across
fields. This situation could make it more difficult to establish priorities
and intermediate endpoints or milestones, which are essential for attain-
ing the ultimate project goal. The ideal manager for external oversight
would thus have extensive experience in all the relevant disciplines; how-
ever, such individuals may be rare because most current training pro-
grams tend to focus on a single discipline.
Because of these challenges, the industrial model of biomedical re-
search may have much to offer large-scale research projects, even when
they are undertaken with public funds at traditional academic institu-
tions. In industry, projects generally involve many layers of oversight,
and teams often specialize in and are responsible for particular methods
or stages of the work. Yet, even large-scale science projects undertaken in
collaboration with industry or through industry consortia may experi-
ence organizational difficulties if they require groups to mesh dissimilar
organizational schemes and cultures.
Personnel Issues
The challenges involved in organizing and managing a large-scale
science project include questions of staffing and the training of junior
scientists working on the project. As mentioned above, much of the work
in academic research laboratories is done by graduate students and
postdoctoral fellows who are striving to build a scientific reputation and
career. This is viewed as a mutually beneficial arrangement because stu-

dents and fellows provide an inexpensive but highly effective labor pool
in exchange for training and future career opportunities based on profes-
sional recognition for the publications they produce. However, this aca-
demic career track may not mesh well with the goals, products, and
timeframe of many large-scale projects. Students who are assigned to
work on a small piece of a large project may spend many years making a
valuable contribution, but emerge without a significant publication record
on which to base their career advancement. They may also fail to derive
the crucial breadth of training or experience students obtain by working
on and developing a smaller, independent project. As a result, it may be
most appropriate to rely more on technical staff than on students when
undertaking a long-term, product-oriented large-scale project.
Information Sharing and Intellectual Property Concerns

The success of big-science projects in fields such as high-energy
physics has been attributed in part to the fact that the products of the
research have no commercial value, and thus the scientists involved in a
project are quite willing to share results and information (Kevles and
Hood, 1992). In contrast, many large-scale projects in biomedical re-
search have substantial commercial value, making it less likely that data
and reagents will be freely shared. The potential profits to be gained in
developing new drugs or other medically applicable technologies are
enormous, and many products of large-scale projects can be used as
tools in the development of such drugs and technologies. However,
when many different research tools are needed to develop a clinically
applicable product, aggressive enforcement of patents and pursuit of
licensing revenues associated with those tools could potentially hamper
the progress of research. As a result, there have been many debates
about access to biological data and the merit and appropriate use of
patenting and licensing of research tools in biomedicine (NIH, 1998;
Heller and Eisenberg, 1998). The challenge is to strike a balance between
patent protection and public access so that institutions are willing to
take the risks and make the commitments necessary to develop new
products with medical and commercial value without significantly im-
peding the progress of research in the field as a whole.
Projects funded by federal agencies may be more apt than those funded
by private industry to rapidly place results into publicly accessible data-
bases and to forego the potential revenues of patenting and licensing the
products of the research. Again, however, there are no absolute distinctions
between publicly and privately funded research with regard to these issues
(Eisenberg, 2000). For example, some projects funded largely by industry
consortia (such as the Single Nucleotide Polymorphisms [SNP] Consor-

tium1) have policies regarding the creation of unencumbered public-domain

database resources similar to those of the publicly funded HGP. On the
other hand, legislation2 passed in 1980 has encouraged academic scientists
and others with federal funding to patent their findings in order to facilitate
commercial development of the research.
SUMMARY
The ultimate goal of biomedical research, both large- and small-scale,
is to advance knowledge and provide useful innovations to society. De-
termining the best and most efficient method for accomplishing that goal,
however, is a continuing and evolving challenge. A review and assess-
ment of large-scale science in biomedical research is warranted at this
time because it is a relatively new concept in bioscience in general, and
there is great interest in applying this scientific approach to address ques-
tions in the study of cancer. For the first time, scientists now have the
ability to develop a large infrastructure upon which to base future re-
search. The availability of genome sequences (human as well as model
organisms, such as bacteria, yeast, worm, fruit fly, and mouse) allows for
gene identification, examination of the regulation of gene expression,
cross-species comparisons, and the study of polymorphisms in popula-
tions. Messenger RNA profiles can be generated to study the normal
function and pathology of different tissues. Technology is available to
study the structure and function of proteins, and their dependence on
chemical modification and location within cells. Further improvements in
experimental technologies and the informatics tools needed to process the
information they generate will likely continue to enhance the speed and
scale with which these resources can be generated and put to use.
When is a large-scale approach suitable for biomedical research, and
what can we do to facilitate such efforts when they are deemed appropri-
ate? The goals of this report are to examine the potential contributions of
large-scale science to biomedical research, to identify impediments to ap-
plying the large-scale approach effectively, and to recommend ways of
improving the process for future endeavors should they be undertaken.
1 The SNP Consortium is composed of the Wellcome Trust and 11 pharmaceutical and
technological companies: APBiotech, AstraZeneca PLC, Aventis, Bayer AG, Bristol-Meyers
Squibb Company, F. Hoffmann-LaRoche, Glaxo Wellcome PLC, IBM, Motorola, Novartis,
Pfizer Inc., Searle, and SmithKline Beecham PLC. See <http://snp.cshl.org/>.
2 The Bayh-Dole Act and the Stevenson-Wydler Technology Innovation Act encouraged
organizations to retain certain patent rights in government-sponsored research, and per-
mitted the funded entity to transfer the technology to third parties. For more detail, see
Chapter 7.

Models of Large-Scale Science
T
o further elaborate on the concept of large-scale biomedical
science as defined in this report, this chapter provides an
overview of several examples of past and current large-scale
projects or strategies in biology and other fields. It begins with a sum-
mary of the Human Genome Project (HGP), the largest and most visible
large-scale science project in biology to date. Many examples are drawn
from NCI, in part because NCI has a longer history and more extensive
ex-perience with directed, large-scale projects compared to other branches
of NIH, and also because a major focus of this report is on cancer re-
search. Several initiatives recently launched by other branches of NIH are
described in detail, followed by examples of National Science Founda-
tion (NSF) programs, industry consortia, public–private collaborations,
and initiatives sponsored by private foundations. The chapter concludes
with an example of a nonbiology model of large-scale science for con-
trast—that of the Defense Advanced Research Projects Agency (DARPA).
The DARPA model is commonly cited as a potential strategy for under-
taking large-scale, high-risk, and goal-oriented research, but this model
has rarely been replicated in biology. A review of federally funded large-
scale research projects in nonbiology fields such as high-energy physics
is provided in the Appendix.
The common theme among the examples described in this chapter is
that they are all formal programs launched by funding agencies, founda-
tions, or industry. There is certainly no shortage of other ideas for poten-
tial large-scale biomedical research projects among scientists. Without an

29 reserved.
Exploring the Variety of Random
Documents with Different Content
Mamouche
Mamouche stood within the open doorway, which he had just

entered. It was night; the rain was falling in torrents, and the water
trickled from him as it would have done from an umbrella, if he had
carried one.
Old Doctor John-Luis, who was toasting his feet before a blazing
hickory-wood fire, turned to gaze at the youngster through his
spectacles. Marshall, the old negro who had opened the door at the
boy’s knock, also looked down at him, and indignantly said:
“G’long back on de gall’ry an’ drip yo’se’f! W’at Cynthy gwine say
tomorrow w’en she see dat flo’ mess’ up dat away?”
“Come to the fire and sit down,” said Doctor John-Luis.
Doctor John-Luis was a bachelor. He was small and thin; he wore
snuff-colored clothes that were a little too large for him, and
spectacles. Time had not deprived him of an abundant crop of hair
that had once been red, and was not now more than half-bleached.
The boy looked irresolutely from master to man; then went and
sat down beside the fire on a splint-bottom chair. He sat so close to
the blaze that had he been an apple he would have roasted. As he
was but a small boy, clothed in wet rags, he only steamed.
Marshall grumbled audibly, and Doctor John-Luis continued to
inspect the boy through his glasses.
“Marsh, bring him something to eat,” he commanded, tentatively.
Marshall hesitated, and challenged the child with a speculating
look.
“Is you w’ite o’ is you black?” he asked. “Dat w’at I wants ter
know ’fo’ I kiar’ victuals to yo in de settin’-room.”
“I’m w’ite, me,” the boy responded, promptly.
“I ain’t disputin’; go ahead. All right fer dem w’at wants ter take
yo’ wud fer it.” Doctor John-Luis coughed behind his hand and said
nothing.
Marshall brought a platter of cold food to the boy, who rested the
dish upon his knees and ate from it with keen appetite.
“Where do you come from?” asked Doctor John-Luis, when his
caller stopped for breath. Mamouche turned a pair of big, soft, dark
eyes upon his questioner.
“I come frum Cloutierville this mo’nin’. I been try to git to the
twenty-fo’-mile ferry w’en de rain ketch me.”
“What were you going to do at the twenty-four-mile ferry?”
The boy gazed absently into the fire. “I don’ know w’at I was goin’
to do yonda to the twenty-fo’-mile ferry,” he said.
“Then you must be a tramp, to be wandering aimlessly about the
country in that way!” exclaimed the doctor.
“No; I don’ b’lieve I’m a tramp, me.” Mamouche was wriggling his
toes with enjoyment of the warmth and palatable food.
“Well, what’s your name?” continued Doctor John-Luis.
“My name it’s Mamouche.”
“‘Mamouche.’ Fiddlesticks! That’s no name.”
The boy looked as if he regretted the fact, while not being able to
help it.
“But my pa, his name it was Mathurin Peloté,” he offered in some
palliation.
“Peloté! Peloté!” mused Doctor John-Luis. “Any kin to Théodule
Peloté who lived formerly in Avoyelles parish?”
“W’y, yas!” laughed Mamouche. “Théodule Peloté, it was my
gran’pa.”
“Your grandfather? Well, upon my word!” He looked again,
critically, at the youngster’s rags. “Then Stéphanie Galopin must
have been your grandmother!”
“Yas,” responded Mamouche, complacently; “that who was my
gran’ma. She die two year ago down by Alexandria.”
“Marsh,” called Doctor John-Luis, turning in his chair, “bring him a
mug of milk and another piece of pie!”
When Mamouche had eaten all the good things that were set
before him, he found that one side of him was quite dry, and he
transferred himself over to the other corner of the fire so as to turn
to the blaze the side which was still wet.
The action seemed to amuse Doctor John-Luis, whose old head
began to fill with recollections.
“That reminds me of Théodule,” he laughed. “Ah, he was a great
fellow, your father, Théodule!”
“My gran’pa,” corrected Mamouche.
“Yes, yes, your grandfather. He was handsome; I tell you, he was
good-looking. And the way he could dance and play the fiddle and
sing! Let me see, how did that song go that he used to sing when
we went out serenading: ‘A ta—à ta—’
‘A ta fenêtre
Daignes paraître—tra la la la!’”
Doctor John-Luis’s voice, even in his youth, could not have been
agreeable; and now it bore no resemblance to any sound that
Mamouche had ever heard issue from a human throat. The boy
kicked his heels and rolled sideward on his chair with enjoyment.
Doctor John-Luis laughed even more heartily, finished the stanza,
and sang another one through.
“That’s what turned the girls’ heads, I tell you, my boy,” said he,
when he had recovered his breath; “that fiddling and dancing and
tra la la.”
During the next hour the old man lived again through his youth;
through any number of alluring experiences with his friend
Théodule, that merry fellow who had never done a steady week’s
work in his life; and Stéphanie, the pretty Acadian girl, whom he had
never wholly understood, even to this day.
It was quite late when Doctor John-Luis climbed the stairs that led
from the sitting-room up to his bedchamber. As he went, followed by
the ever attentive Marshall, he was singing:
“A ta fenêtre
Daignes paraître,”
but very low, so as not to awaken Mamouche, whom he left sleeping

upon a bed that Marshall at his order had prepared for the boy
beside the sitting-room fire.
At a very early hour next morning Marshall appeared at his
master’s bedside with the accustomed morning coffee.
“What is he doing?” asked Doctor John-Luis, as he sugared and
stirred the tiny cup of black coffee.
“Who dat, sah?”
“Why, the boy, Mamouche. What is he doing?”
“He gone, sah. He done gone.”
“Gone!”
“Yas, sah. He roll his bed up in de corner; he onlock de do’; he
gone. But de silver an’ ev’thing dah; he ain’t kiar’ nuttin’ off.”
“Marshall,” snapped Doctor John-Luis, ill-humoredly, “there are
times when you don’t seem to have sense and penetration enough
to talk about! I think I’ll take another nap,” he grumbled, as he
turned his back upon Marshall. “Wake me at seven.”
It was no ordinary thing for Doctor John-Luis to be in a bad
humor, and perhaps it is not strictly true to say that he was now. He
was only in a little less amiable mood than usual when he pulled on
his high rubber boots and went splashing out in the wet to see what
his people were doing.
He might have owned a large plantation had he wished to own
one, for a long life of persistent, intelligent work had left him with a
comfortable fortune in his old age; but he preferred the farm on
which he lived contentedly and raised an abundance to meet his
modest wants.
He went down to the orchard, where a couple of men were
busying themselves in setting out a line of young fruit-trees.
“Tut, tut, tut!” They were doing it all wrong; the line was not
straight; the holes were not deep. It was strange that he had to
come down there and discover such things with his old eyes!
He poked his head into the kitchen to complain to Prudence about
the ducks that she had not seasoned properly the day before, and to
hope that the accident would never occur again.
He tramped over to where a carpenter was working on a gate;
securing it—as he meant to secure all the gates upon his place—with
great patent clamps and ingenious hinges, intended to baffle utterly
the designs of the evil-disposed persons who had lately been
tampering with them. For there had been a malicious spirit abroad,
who played tricks, it seemed, for pure wantonness upon the farmers
and planters, and caused them infinite annoyance.
As Dr. John-Luis contemplated the carpenter at work, and
remembered how his gates had recently all been lifted from their
hinges one night and left lying upon the ground, the provoking
nature of the offense dawned upon him as it had not done before.
He turned swiftly, prompted by a sudden determination, and re-
entered the house.
Then he proceeded to write out in immense black characters a
half-dozen placards. It was an offer of twenty-five dollars’ reward for
the capture of the person guilty of the malicious offence already
described. These placards were sent abroad with the same eager
haste that had conceived and executed them.
After a day or two, Doctor John-Luis’ ill humor had resolved itself
into a pensive melancholy.
“Marsh,” he said, “you know, after all, it’s rather dreary to be living
alone as I do, without any companion—of my own color, you
understand.”
“I knows dat, sah. It sho’ am lonesome,” replied the sympathetic
Marshall.
“You see, Marsh, I’ve been thinking lately,” and Doctor John-Luis
coughed, for he disliked the inaccuracy of that “lately.” “I’ve been
thinking that this property and wealth that I’ve worked so hard to
accumulate, are after all doing no permanent, practical good to any
one. Now, if I could find some well-disposed boy whom I might train
to work, to study, to lead a decent, honest life—a boy of good heart
who would care for me in my old age; for I am still comparatively—
hem—not old? hey, Marsh?”
“Dey ain’t one in de pa’ish hole yo’ own like you does, sah.”
“That’s it. Now, can you think of such a boy? Try to think.”
Marshall slowly scratched his head and looked reflective.
“If you can think of such a boy,” said Doctor John-Luis, “you might
bring him here to spend an evening with me, you know, without
hinting at my intentions, of course. In that way I could sound him;
study him up, as it were. For a step of such importance is not to be
taken without due consideration, Marsh.”
Well, the first whom Marshall brought was one of Baptiste
Choupic’s boys. He was a very timid child, and sat on the edge of his
chair, fearfully. He replied in jerky mono-*syllables when Doctor
John-Luis spoke to him, “Yas, sah—no, sah,” as the case might be;
with a little nervous bob of the head.
His presence made the doctor quite uncomfortable. He was glad
to be rid of the boy at nine o’clock, when he sent him home with
some oranges and a few sweetmeats.
Then Marshall had Theodore over; an unfortunate selection that
evinced little judgment on Marshall’s part. Not to mince matters, the
boy was painfully forward. He monopolized the conversation; asked
impertinent questions and handled and inspected everything in the
room. Dr. John-Luis sent him home with an orange and not a single
sweet.
Then there was Hyppolite, who was too ugly to be thought of; and
Cami, who was heavy and stupid, and fell asleep in his chair with his
mouth wide open. And so it went. If Doctor John-Luis had hoped in
the company of any of these boys to repeat the agreeable evening
he had passed with Mamouche, he was sadly deceived.
At last he instructed Marshall to discontinue the search of that
ideal companion he had dreamed of. He was resigned to spend the
remainder of his days without one.
Then, one day when it was raining again, and very muddy and
chill, a red-faced man came driving up to Doctor John-Luis’ door in a
dilapidated buggy. He lifted a boy from the vehicle, whom he held
with a vise-like clutch, and whom he straightway dragged into the
astonished presence of Doctor John-Luis.
“Here he is, sir,” shouted the red-faced man. “We’ve got him at
last! Here he is.”
It was Mamouche, covered with mud, the picture of misery. Doctor
John-Luis stood with his back to the fire. He was startled, and visibly
and painfully moved at the sight of the boy.
“Is it possible!” he exclaimed. “Then it was you, Mamouche, who
did this mischievous thing to me? Lifting my gates from their hinges;
letting the chickens in among my flowers to ruin them; and the hogs
and cattle to trample and uproot my vegetables!”
“Ha! ha!” laughed the red-faced man, “that game’s played out,
now;” and Doctor John-Luis looked as if he wanted to strike him.
Mamouche seemed unable to reply. His lower lip was quivering.
“Yas, it’s me!” he burst out. “It’s me w’at take yo’ gates off the
hinge. It’s me w’at turn loose Mr. Morgin’s hoss, w’en Mr. Morgin was
passing veillée wid his sweetheart. It’s me w’at take down Ma’ame
Angèle’s fence, an’ lef her calf loose to tramp in Mr. Billy’s cotton. It’s
me w’at play like a ghos’ by the graveyard las’ Toussaint to scare the
darkies passin’ in the road. It’s me w’at—”
The confession had burst out from the depth of Mamouche’s heart
like a torrent, and there is no telling when it would have stopped if
Doctor John-Luis had not enjoined silence.
“And pray tell me,” he asked, as severely as he could, “why you
left my house like a criminal, in the morning, secretly?”
The tears had begun to course down Mamouche’s brown cheeks.
“I was ’shame’ of myse’f, that’s w’y. If you wouldn’ gave me no
suppa, an’ no bed, an’ no fire, I don’ say.’ I wouldn’ been ’shame’
then.”
“Well, sir,” interrupted the red-faced man, “you’ve got a pretty
square case against him, I see. Not only for malicious trespass, but
of theft. See this bolt?” producing a piece of iron from his coat
pocket. “That’s what gave him away.”
“I en’t no thief!” blurted Mamouche, indignantly. “It’s one piece o’
iron w’at I pick up in the road.”
“Sir,” said Doctor John-Luis with dignity, “I can understand how
the grandson of Théodule Peloté might be guilty of such mischievous
pranks as this boy has confessed to. But I know that the grandson of
Stéphanie Galopin could not be a thief.”
And he at once wrote out the check for twenty-five dollars, and
handed it to the red-faced man with the tips of his fingers.
It seemed very good to Doctor John-Luis to have the boy sitting
again at his fireside; and so natural, too. He seemed to be the
incarnation of unspoken hopes; the realization of vague and fitful
memories of the past.
When Mamouche kept on crying, Doctor John-Luis wiped away the
tears with his own brown silk handkerchief.
“Mamouche,” he said, “I want you to stay here; to live here with
me always. To learn how to work; to learn how to study; to grow up
to be an honorable man. An honorable man, Mamouche, for I want
you for my own child.”
His voice was pretty low and husky when he said that.
“I shall not take the key from the door to-*night,” he continued.
“If you do not choose to stay and be all this that I say, you may
open the door and walk out. I shall use no force to keep you.”
“What is he doing, Marsh?” asked Doctor John-Luis the following

morning, when he took the coffee that Marshall had brought to him
in bed.
“Who dat, sah?”
“Why, the boy Mamouche, of course. What is he doing?”
Marshall laughed.
“He kneelin’ down dah on de flo’. He keep on sayin’, ‘Hail, Mary,
full o’ grace, de Lord is wid dee. Hail, Mary, full o’ grace’—t’ree, fo’
times, sah. I tell ’im, ‘W’at you sayin’ yo’ prayer dat away, boy?’ He
’low dat w’at his gran’ma lam ’im, ter keep outen mischief. W’en de
devil say, ‘Take dat gate offen de hinge; do dis; do dat,’ he gwine say
t’ree Hail Mary, an’ de devil gwine tu’n tail an’ run.”
“Yes, yes,” laughed Doctor John-Luis. “That’s Stéphanie all over.”
“An’ I tell ’im: See heah, boy, you drap a couple o’ dem Hail Mary,
an’ quit studyin’ ’bout de devil, an’ sot yo’se’f down ter wuk. Dat the
oniest way to keep outen mischief.”
“What business is it of yours to interfere?” broke in Doctor John-
Luis, irritably. “Let the boy do as his grandmother instructed him.”
“I ain’t desputin’, sah,” apologized Marshall.
“But you know, Marsh,” continued the doctor, recovering his usual
amiability. “I think we’ll be able to do something with the boy. I’m
pretty sure of it. For, you see, he has his grandmother’s eyes; and
his grandmother was a very intelligent woman; a clever woman,
Marsh. Her one great mistake was when she married Théodule
Peloté.”
A Sentimental Soul
A Sentimental Soul
I.
Lacodie stayed longer than was his custom in Mamzelle Fleurette’s
little store that evening. He had been tempted by the vapid
utterances of a conservative bellhanger to loudly voice his radical
opinions upon the rights and wrongs of humanity when he finally
laid his picayune down upon Mamzelle Fleurette’s counter and
helped himself to l’Abeille from the top of the diminished pile of
newspapers which stood there.
He was small, frail and hollow-chested, but his head was
magnificent with its generous adornment of waving black hair; its
sunken eyes that glowed darkly and steadily and sometimes flamed,
and its moustaches which were formidable.
“Eh bien, Mamzelle Fleurette, à demain, à demain!” and he waved
a nervous good-bye as he let himself quickly and noiselessly out.
However violent Lacodie might be in his manner toward
conservatives, he was always gentle, courteous and low-voiced with
Mamzelle Fleurette, who was much older than he, much taller; who
held no opinions, and whom he pitied, and even in a manner
revered. Mamzelle Fleurette at once dismissed the bell-hanger, with
whom, on general principles, she had no sympathy.
She wanted to close the store, for she was going over to the
cathedral to confession. She stayed a moment in the doorway
watching Lacodie walk down the opposite side of the street. His step
was something between a spring and a jerk, which to her partial
eyes seemed the perfection of motion. She watched him until he
entered his own small low doorway, over which hung a huge wooden
key painted red, the emblem of his trade.
For many months now, Lacodie had been coming daily to
Mamzelle Fleurette’s little notion store to buy the morning paper,
which he only bought and read, however, in the afternoon. Once he
had crossed over with his box of keys and tools to open a cupboard,
which would unlock for no inducements of its owner. He would not
suffer her to pay him for the few moments’ work; it was nothing, he
assured her; it was a pleasure; he would not dream of accepting
payment for so trifling a service from a camarade and fellow-worker.
But she need not fear that he would lose by it, he told her with a
laugh; he would only charge an extra quarter to the rich lawyer
around the corner, or to the top-lofty druggist down the street when
these might happen to need his services, as they sometimes did.
This was an alternative which seemed far from right and honest to
Mamzelle Fleurette. But she held a vague understanding that men
were wickeder in many ways than women; that ungodliness was
constitutional with them, like their sex, and inseparable from it.
Having watched Lacodie until he disappeared within his shop, she
retired to her room, back of the store, and began her preparations to
go out. She brushed carefully the black alpaca skirt, which hung in
long nunlike folds around her spare figure. She smoothed down the
brown, ill-fitting basque, and readjusted the old-fashioned, rusty
black lace collar which she always wore. Her sleek hair was painfully
and suspiciously black. She powdered her face abundantly with
poudre de riz before starting out, and pinned a dotted black lace veil
over her straw bonnet. There was little force or character or
anything in her withered face, except a pathetic desire and appeal to
be permitted to exist.
Mamzelle Fleurette did not walk down Chartres street with her
usual composed tread; she seemed preoccupied and agitated. When
she passed the locksmith’s shop over the way and heard his voice
within, she grew tremulously self-conscious, fingering her veil,
swishing the black alpaca and waving her prayer book about with
meaningless intention.
Mamzelle Fleurette was in great trouble; trouble which was so
bitter, so sweet, so bewildering, so terrifying! It had come so
stealthily upon her she had never suspected what it might be. She
thought the world was growing brighter and more beautiful; she
thought the flowers had redoubled their sweetness and the birds
their song, and that the voices of her fellow-creatures had grown
kinder and their faces truer.
The day before Lacodie had not come to her for his paper. At six
o’clock he was not there, at seven he was not there, nor at eight,
and then she knew he would not come. At first, when it was only a
little past the time of his coming, she had sat strangely disturbed
and distressed in the rear of the store, with her back to the door.
When the door opened she turned with fluttering expectancy. It was
only an unhappy-looking child, who wanted to buy some foolscap, a
pencil and an eraser. The next to come in was an old mulatresse,
who was bringing her prayer beads for Mamzelle Fleurette to mend.
The next was a gentleman, to buy the Courier des Etats Unis, and
then a young girl, who wanted a holy picture for her favorite nun at
the Ursulines; it was everybody but Lacodie.
A temptation assailed Mamzelle Fleurette, almost fierce in its
intensity, to carry the paper over to his shop herself, when he was
not there at seven. She conquered it from sheer moral inability to do
anything so daring, so unprecedented. But to-day, when he had
come back and had stayed so long discoursing with the bellhanger, a
contentment, a rapture, had settled upon her being which she could
no longer ignore or mistake. She loved Lacodie. That fact was plain
to her now, as plain as the conviction that every reason existed why
she should not love him. He was the husband of another woman. To
love the husband of another woman was one of the deepest sins
which Mamzelle Fleurette knew; murder was perhaps blacker, but
she was not sure. She was going to confession now. She was going
to tell her sin to Almighty God and Father Fochelle, and ask their
forgiveness. She was going to pray and beg the saints and the Holy
Virgin to remove the sweet and subtle poison from her soul. It was
surely a poison, and a deadly one, which could make her feel that
her youth had come back and taken her by the hand.
II.
Mamzelle Fleurette had been confessing for many years to old
Father Fochelle. In his secret heart he often thought it a waste of his
time and her own that she should come with her little babblings, her
little nothings to him, calling them sins. He felt that a wave of the
hand might brush them away, and that it in a manner compromised
the dignity of holy absolution to pronounce the act over so innocent
a soul.
To-day she had whispered all her shortcomings into his ear
through the grating of the confessional; he knew them so well!
There were many other penitents waiting to be heard, and he was
about to dismiss her with a hasty blessing when she arrested him,
and in hesitating, faltering accents told him of her love for the
locksmith, the husband of another woman. A slap in the face would
not have startled Father Fochelle more forcibly or more painfully.
What soul was there on earth, he wondered, so hedged about with
innocence as to be secure from the machinations of Satan! Oh, the
thunder of indignation that descended upon Mamzelle Fleurette’s
head! She bowed down, beaten to earth beneath it. Then came
questions, one, two, three, in quick succession, that made Mamzelle
Fleurette gasp and clutch blindly before her. Why was she not a
shadow, a vapor, that she might dissolve from before those angry,
penetrating eyes; or a small insect, to creep into some crevice and
there hide herself forevermore?
“Oh, father! no, no, no!” she faltered, “he knows nothing, nothing.
I would die a hundred deaths before he should know, before anyone
should know, besides yourself and the good God of whom I implore
pardon.”
Father Fochelle breathed more freely, and mopped his face with a
flaming bandana, which he took from the ample pocket of his
soutane. But he scolded Mamzelle Fleurette roundly, unpityingly; for
being a fool, for being a sentimentalist. She had not committed
mortal sin, but the occasion was ripe for it; and look to it she must
that she keep Satan at bay with watchfulness and prayer. “Go, my
child, and sin no more.”
Mamzelle Fleurette made a détour in regaining her home by which
she would not have to pass the locksmith’s shop. She did not even
look in that direction when she let herself in at the glass door of her
store.
Some time before, when she was yet ignorant of the motive which
prompted the act, she had cut from a newspaper a likeness of
Lacodie, who had served as foreman of the jury during a prominent
murder trial. The likeness happened to be good, and quite did
justice to the locksmith’s fine physiognomy with its leonine hirsute
adornment. This picture Mamzelle Fleurette had kept hitherto
between the pages of her prayer book. Here, twice a day, it looked
out at her; as she turned the leaves of the holy mass in the morning,
and when she read her evening devotions before her own little home
altar, over which hung a crucifix and a picture of the Empress
Eugénie.
Her first action upon entering her room, even before she unpinned
the dotted veil, was to take Lacodie’s picture from her prayer book
and place it at random between the leaves of a “Dictionnaire de la
Langue Francaise,” which was the undermost of a pile of old books
that stood on the corner of the mantelpiece. Between night and
morning, when she would approach the holy sacrament, Mamzelle
Fleurette felt it to be her duty to thrust Lacodie from her thoughts by
every means and device known to her.
The following day was Sunday, when there was no occasion or
opportunity for her to see the locksmith. Moreover, after partaking of
holy communion, Mamzelle Fleurette felt invigorated; she was
conscious of a new, if fictitious, strength to combat Satan and his
wiles.
On Monday, as the hour approached for Lacodie to appear,
Mamzelle Fleurette became harassed by indecision. Should she call
in the young girl, the neighbor who relieved her on occasion, and
deliver the store into the girl’s hands for an hour or so? This might
be well enough for once in a while, but she could not conveniently
resort to this subterfuge daily. After all, she had her living to make,
which consideration was paramount. She finally decided that she
would retire to her little back room and when she heard the store
door open she would call out:
“Is it you, Monsieur Lacodie? I am very busy; please take your
paper and leave your cinq sous on the counter.” If it happened not to
be Lacodie she would come forward and serve the customer in
person. She did not, of course, expect to carry out this performance
each day; a fresh device would no doubt suggest itself for tomorrow.
Mamzelle Fleurette proceeded to carry out her programme to the
letter.
“Is it you, Monsieur Lacodie?” she called out from the little back
room, when the front door opened. “I am very busy; please take
your paper—”
“Ce n’est pas Lacodie, Mamzelle Fleurette. C’est moi, Augustine.”
It was Lacodie’s wife, a fat, comely young woman, wearing a blue
veil thrown carelessly over her kinky black hair, and carrying some
grocery parcels clasped close in her arms. Mamzelle Fleurette
emerged from the back room, a prey to the most contradictory
emotions; relief and disappointment struggling for the mastery with
her.
“No Lacodie to-day, Mamzelle Fleurette,” Augustine announced
with a certain robust ill-humor; “he is there at home shaking with a
chill till the very window panes rattle. He had one last Friday” (the
day he had not come for his paper) “and now another and a worse
one to-day. God knows, if it keeps on-well, let me have the paper;
he will want to read it to-night when his chill is past.”
Mamzelle Fleurette handed the paper to Augustine, feeling like an
old woman in a dream handing a newspaper to a young woman in a
dream. She had never thought of Lacodie having chills or being ill. It
seemed very strange. And Augustine was no sooner gone than all
the ague remedies she had ever heard of came crowding to
Mamzelle Fleurette’s mind; an egg in black coffee—or was it a lemon
in black coffee? or an egg in vinegar? She rushed to the door to call
Augustine back, but the young woman was already far down the
street.
III.
Augustine did not come the next day, nor the next, for the paper.
The unhappy looking child who had returned for more foolscap,
informed Mamzelle Fleurette that he had heard his mother say that
Monsieur Lacodie was very sick, and the bellhanger had sat up all
night with him. The following day Mamzelle Fleurette saw Choppin’s
coupé pass clattering over the cobblestones and stop before the
locksmith’s door. She knew that with her class it was only in a case
of extremity that the famous and expensive physician was
summoned. For the first time she thought of death. She prayed all
day, silently, to herself, even while waiting upon customers.
In the evening she took an Abeille from the top of the pile on the
counter, and throwing a light shawl over her head, started with the
paper over to the locksmith’s shop. She did not know if she were
committing a sin in so doing. She would ask Father Fochelle on
Saturday, when she went to confession. She did not think it could be
a sin; she would have called long before on any other sick neighbor,
and she intuitively felt that in this distinction might lie the possibility
of sin.
The shop was deserted except for the presence of Lacodie’s little
boy of five, who sat upon the floor playing with the tools and
contrivances which all his days he had coveted, and which all his
days had been denied to him. Mamzelle Fleurette mounted the
narrow stairway in the rear of the shop which led to an upper
landing and then into the room of the married couple. She stood a
while hesitating upon this landing before venturing to knock softly
upon the partly open door through which she could hear their
voices.
“I thought,” she remarked apologetically to Augustine, “that
perhaps Monsieur Lacodie might like to look at the paper and you
had no time to come for it, so I brought it myself.”
“Come in, come in, Mamzelle Fleurette. It’s Mamzelle Fleurette
who comes to inquire about you, Lacodie,” Augustine called out
loudly to her husband, whose half consciousness she somehow
confounded with deafness.
Mamzelle Fleurette drew mincingly forward, clasping her thin
hands together at the waist line, and she peeped timorously at
Lacodie lying lost amid the bedclothes. His black mane was tossed
wildly over the pillow and lent a fictitious pallor to the yellow
waxiness of his drawn features. An approaching chill was sending
incipient shudders through his frame, and making his teeth claque.
But he still turned his head courteously in Mamzelle Fleurette’s
direction.
“Bien bon de votre part, Mamzelle Fleurette—mais c’est fini. J’suis
flambé, flambé, flambé!”
Oh, the pain of it! to hear him in such extremity thanking her for
her visit, assuring her in the same breath that all was over with him.
She wondered how Augustine could hear it so composedly. She
whisperingly inquired if a priest had been summoned.
“Inutile; il n’en veut pas,” was Augustine’s reply. So he would have
no priest at his bedside, and here was a new weight of bitterness for
Mamzelle Fleurette to carry all her days.
She flitted back to her store through the darkness, herself like a
slim shadow. The November evening was chill and misty. A dull
aureole shot out from the feeble gas jet at the corner, only faintly
and for an instant illumining her figure as it glided rapidly and
noiselessly along the banquette. Mamzelle Fleurette slept little and
prayed much that night. Saturday morning Lacodie died. On Sunday
he was buried and Mamzelle Fleurette did not go to the funeral,
because Father Fochelle told her plainly she had no business there.
It seemed inexpressibly hard to Mamzelle Fleurette that she was
not permitted to hold Lacodie in tender remembrance now that he
was dead. But Father Fochelle, with his practical insight, made no
compromise with sentimentality; and she did not question his
authority, or his ability to master the subtleties of a situation utterly
beyond reach of her own powers.
It was no longer a pleasure for Mamzelle Fleurette to go to
confession as it had formerly been. Her heart went on loving Lacodie
and her soul went on struggling; for she made this delicate and
puzzling distinction between heart and soul, and pictured the two as
set in a very death struggle against each other.
“I cannot help it, father. I try, but I cannot help it. To love him is
like breathing; I do not know how to help it. I pray, and pray, and it
does no good, for half of my prayers are for the repose of his soul. It
surely cannot be a sin, to pray for the repose of his soul?”
Father Fochelle was heartily sick and tired of Mamzelle Fleurette
and her stupidities. Oftentimes he was tempted to drive her from the
confessional, and forbid her return until she should have regained a
rational state of mind. But he could not withhold absolution from a
penitent who, week after week, acknowledged her shortcoming and
strove with all her faculties to overcome it and atone for it.
IV.
Augustine had sold out the locksmith’s shop and the business, and
had removed further down the street over a bakery. Out of her
window she had hung a sign, “Blanchisseuse de Fin.” Often, in
passing by, Mamzelle Fleurette would catch a glimpse of Augustine
up at the window, plying the irons; her sleeves rolled to the elbows,
baring her round, white arms, and the little black curls all moist and
tangled about her face. It was early spring then, and there was a
languor in the air; an odor of jasmine in every passing breeze; the
sky was blue, unfathomable, and fleecy white; and people along the
narrow street laughed, and sang, and called to one another from
windows and doorways. Augustine had set a pot of rose-geranium
on her window sill and hung out a bird cage.
Once, Mamzelle Fleurette in passing on her way to confession
heard her singing roulades, vying with the bird in the cage. Another
time she saw the young woman leaning with half her body from the
window, exchanging pleasantries with the baker standing beneath
on the banquette.
Still, a little later, Mamzelle Fleurette began to notice a handsome
young fellow often passing the store. He was jaunty and debonnaire
and wore a rich watchchain, and looked prosperous. She knew him
quite well as a fine young Gascon, who kept a stall in the French
Market, and from whom she had often bought charcuterie. The
neighbors told her the young Gascon was paying his addresses to
Mme. Lacodie. Mamzelle Fleurette shuddered. She wondered if
Lacodie knew! The whole situation seemed suddenly to shift its
base, causing Mamzelle Fleurette to stagger. What ground would her
poor heart and soul have to do battle upon now?
She had not yet had time to adjust her conscience to the altered
conditions when one Saturday afternoon, as she was about to start
out to confession, she noticed an unusual movement down the
street. The bellhanger, who happened to be presenting himself in
the character of a customer, informed her that it was nothing more
nor less than Mme. Lacodie returning from her wedding with the
Gascon. He was black and bitter with indignation, and thought she
might at least have waited for the year to be out. But the charivari
was already on foot; and Mamzelle need not feel alarmed if, in the
night, she heard sounds and clamor to rouse the dead as far away
as Metairie ridge.
Mamzelle Fleurette sank down in a chair, trembling in all her
members. She faintly begged the bellhanger to pour her a glass of
water from the stone pitcher behind the counter. She fanned herself
and loosened her bonnet strings. She sent the bell hanger away.
She nervously pulled off her rusty black kid gloves, and ten times
more nervously drew them on again. To a little customer, who came
in for chewing gum, she handed a paper of pins.
There was a great, a terrible upheaval taking place in Mamzelle
Fleurette’s soul. She was preparing for the first time in her life to
take her conscience into her own keeping.
When she felt herself sufficiently composed to appear decently
upon the street, she started out to confession. She did not go to
Father Fochelle. She did not even go to the Cathedral; but to a
church which was much farther away, and to reach which she had to
spend a picayune for car fare.
Mamzelle Fleurette confessed herself to a priest who was utterly
new and strange to her. She told him all her little venial sins, which
she had much difficulty in bringing to a number of any dignity and
importance whatever. Not once did she mention her love for Lacodie,
the dead husband of another woman.
Mamzelle Fleurette did not ride back to her home; she walked.
The sensation of walking on air was altogether delicious; she had
never experienced it before. A long time she stood contemplative
before a shop window in which were displayed wreaths, mottoes,
emblems, designed for the embellishment of tombstones. What a
sweet comfort it would be, she reflected, on the 1st of November to
carry some such delicate offering to Lacodie’s last resting place.
Might not the sole care of his tomb devolve upon her, after all! The
possibility thrilled her and moved her to the heart. What thought
would the merry Augustine and her lover-husband have for the dead
lying in cemeteries!
When Mamzelle Fleurette reached home she went through the
store directly into her little back room. The first thing which she did,
even before unpinning the dotted lace veil, was to take the
“Dictionnaire de La Langue Francaise” from beneath the pile of old
books on the mantelpiece. It was not easy to find Lacodie’s picture
hidden somewhere in its depths. But the search afforded her almost
a sensuous pleasure; turning the leaves slowly back and forth.
When she had secured the likeness she went into the store and
from her showcase selected a picture frame—the very handsomest
there; one of those which sold for thirty-five cents.
Into the frame Mamzelle Fleurette neatly and deftly pasted
Lacodie’s picture. Then she re-entered her room and deliberately
hung it upon the wall—between the crucifix and the portrait of
Empress Eugènie—and she did not care if the Gascon’s wife ever
saw it or not.
Dead Men’s Shoes
Dead Men’s Shoes
It never occurred to any person to wonder what would befall Gilma

now that “le vieux Gamiche” was dead. After the burial people
went their several ways, some to talk over the old man and his
eccentricities, others to forget him before nightfall, and others to
wonder what would become of his very nice property, the hundred-
acre farm on which he had lived for thirty years, and on which he
had just died at the age of seventy.
If Gilma had been a child, more than one motherly heart would
have gone out to him. This one and that one would have bethought
them of carrying him home with them; to concern themselves with
his present comfort, if not his future welfare. But Gilma was not a
child. He was a strapping fellow of nineteen, measuring six feet in
his stockings, and as strong as any healthy youth need be. For ten
years he had lived there on the plantation with Monsieur Gamiche;
and he seemed now to have been the only one with tears to shed at
the old man’s funeral.
Gamiche’s relatives had come down from Caddo in a wagon the
day after his death, and had settled themselves in his house. There
was Septime, his nephew, a cripple, so horribly afflicted that it was
distressing to look at him. And there was Septime’s widowed sister,
Ma’me Brozé, with her two little girls. They had remained at the
house during the burial, and Gilma found them still there upon his
return.
The young man went at once to his room to seek a moment’s
repose. He had lost much sleep during Monsieur Gamiche’s illness;
yet, he was in fact more worn by the mental than the bodily strain of
the past week.
But when he entered his room, there was something so changed
in its aspect that it seemed no longer to belong to him. In place of
his own apparel which he had left hanging on the row of pegs, there
were a few shabby little garments and two battered straw hats, the
property of the Brozé children. The bureau drawers were empty,
there was not a vestige of anything belonging to him remaining in
the room. His first impression was that Ma’me Brozé had been
changing things around and had assigned him to some other room.
But Gilma understood the situation better when he discovered
every scrap of his personal effects piled up on a bench outside the
door, on the back or “false” gallery. His boots and shoes were under
the bench, while coats, trousers and underwear were heaped in an
indiscriminate mass together.
The blood mounted to his swarthy face and made him look for the
moment like an Indian. He had never thought of this. He did not
know what he had been thinking of; but he felt that he ought to
have been prepared for anything; and it was his own fault if he was
not. But it hurt. This spot was “home” to him against the rest of the
world. Every tree, every shrub was a friend; he knew every patch in
the fences; and the little old house, gray and weather-beaten, that
had been the shelter of his youth, he loved as only few can love
inanimate things. A great enmity arose in him against Ma’me Brozé.
She was walking about the yard, with her nose in the air, and a
shabby black dress trailing behind her. She held the little girls by the
hand.
Gilma could think of nothing better to do than to mount his horse
and ride away—anywhere. The horse was a spirited animal of great
value. Monsieur Gamiche had named him “Jupiter” on account of his
proud bearing, and Gilma had nicknamed him “Jupe,” which seemed
to him more endearing and expressive of his great attachment to the
fine creature. With the bitter resentment of youth, he felt that “Jupe”
was the only friend remaining to him on earth.
He had thrust a few pieces of clothing in his saddlebags and had
requested Ma’me Brozé, with assumed indifference, to put his
remaining effects in a place of safety until he should be able to send
for them.
As he rode around by the front of the house, Septime, who sat on
the gallery all doubled up in his uncle Gamiche’s big chair, called out:
“Hé, Gilma! w’ere you boun’ fo’?”
“I’m goin’ away,” replied Gilma, curtly, reining his horse.
“That’s all right; but I reckon you might jus’ as well leave that hoss
behine you.”
“The hoss is mine,” returned Gilma, as quickly as he would have
returned a blow.
“We’ll see ’bout that li’le later, my frien’. I reckon you jus’ well turn
’im loose.”
Gilma had no more intention of giving up his horse than he had of
parting with his own right hand. But Monsieur Gamiche had taught
him prudence and respect for the law. He did not wish to invite
disagreeable complications. So, controlling his temper by a supreme
effort, Gilma dismounted, unsaddled the horse then and there, and
led it back to the stable. But as he started to leave the place on foot,
he stopped to say to Septime:
“You know, Mr. Septime, that hoss is mine; I can collec’ a hundred
aff’davits to prove it. I’ll bring them yere in a few days with a
statement f’om a lawyer; an’ I’ll expec’ the hoss an’ saddle to be
turned over to me in good condition.”
“That’s all right. We’ll see ’bout that. Won’t you stay fo’ dinna?”
“No, I thank you, sah; Ma’me Brozé already ask’ me.” And Gilma
strode away, down the beaten footpath that led across the sloping
grassplot toward the outer road.
A definite destination and a settled purpose ahead of him seemed
to have revived his flagging energies of an hour before. It was with
no trace of fatigue that he stepped out bravely along the wagon-road
that skirted the bayou.
It was early spring, and the cotton had already a good stand. In
some places the negroes were hoeing. Gilma stopped alongside the
rail fence and called to an old negress who was plying her hoe at no
great distance.
“Hello, Aunt Hal’fax! see yere.”
She turned, and immediately quitted her work to go and join him,
bringing her hoe with her across her shoulder. She was large-boned
and very black. She was dressed in the deshabille of the field.
“I wish you’d come up to yo’ cabin with me a minute, Aunt Hally,”
he said; “I want to get an aff’davit f’om you.”
She understood, after a fashion, what an affidavit was; but she
couldn’t see the good of it.
“I ain’t got no aff’davis, boy; you g’long an’ don’ pesta me.”
“’Twon’t take you any time, Aunt Hal’fax. I jus’ want you to put yo’
mark to a statement I’m goin’ to write to the effec’ that my hoss,
Jupe, is my own prop’ty; that you know it, an’ willin’ to swear to it.”
“Who say Jupe don’ b’long to you?” she questioned cautiously,
leaning on her hoe.
He motioned toward the house.
“Who? Mista Septime and them?”
“Yes.”
“Well, I reckon!” she exclaimed, sympathetically.
“That’s it,” Gilma went on; “an’ nex’ thing they’ll be sayin’ yo’ ole
mule, Policy, don’t b’long to you.”
She started violently.
“Who say so?”
“Nobody. But I say, nex’ thing, that’ w’at they’ll be sayin’.”
She began to move along the inside of the fence, and he turned to
keep pace with her, walking on the grassy edge of the road.
“I’ll jus’ write the aff’davit, Aunt Hally, an’ all you got to do”—
“You know des well as me dat mule mine. I done paid ole Mista
Gamiche fo’ ’im in good cotton; dat year you falled outen de
puckhorn tree; an’ he write it down hisse’f in his ’count book.”
Gilma did not linger a moment after obtaining the desired
statement from Aunt Halifax. With the first of those “hundred
affidavits” that he hoped to secure, safe in his pocket, he struck out
across the country, seeking the shortest way to town.
Aunt Halifax stayed in the cabin door.

Buy ebook Large Scale Biomedical Science Exploring Strategies for Future Research 1st Edition Committee On Large-Scale Science And Cancer Research cheap price

Uploaded by

Copyright:

Available Formats

Buy ebook Large Scale Biomedical Science Exploring Strategies for Future Research 1st Edition Committee On Large-Scale Science And Cancer Research cheap price

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Buy ebook Large Scale Biomedical Science Exploring Strategies for Future Research 1st Edition Committee On Large-Scale Science And Cancer Research cheap price

Uploaded by

Copyright:

Available Formats

Download the full version of the ebook at

Large Scale Biomedical Science Exploring

Explore and download more ebook at https://ebookultra.com

Large Scale Geometry Second Edition Piotr Nowak

Creativity In Large scale Contexts 1st Edition Jonathan S.

Mastering Kubernetes Large scale container deployment and

Large Scale Software Architecture A Practical Guide using

Large Scale Ecology Model Systems to Global Perspectives

Emergent semantics interoperability in large scale

Subverting Borders Doing Research on Smuggling and Small

Energy From the Desert Practical Proposals for Very Large

Committee on Large-Scale Science and Cancer Research

National Cancer Policy Board

THE NATIONAL ACADEMIES PRESS

Copyright © 2003 National Academy of Sciences. All rights reserved.

Library of Congress Cataloging-in-Publication Data

Large-scale biomedical science : exploring strategies for future

Copyright 2003 by the National Academy of Sciences. All rights reserved.

Printed in the United States of America.

Copyright © 2003 National Academy of Sciences. All rights reserved.

The National Academy of Sciences is a private, nonprofit, self-perpetuating soci-

The Institute of Medicine was established in 1970 by the National Academy of

Copyright © 2003 National Academy of Sciences. All rights reserved.

COMMITTEE ON LARGE-SCALE SCIENCE

*JOSEPH V. SIMONE, M.D. (Chair), Simone Consulting,

*KATHLEEN H. MOONEY, Ph.D. Professor and Peery Presidential

Mina J. Bissell, Ph.D. Distinguished Scientist, Life Sciences

Although the reviewers listed above have provided many construc-

The committee gratefully acknowledges the contributions of many

Copyright © 2003 National Academy of Sciences. All rights reserved.

AAAS – American Association for the Advancement of Science

BAA – Broad Agency Announcement

CDC – Centers for Disease Control and Prevention

DARPA – The Defense Advanced Research Projects Agency

EDRN – The Early Detection Research Network

FDA – Food and Drug Administration

GPRA – Government Performance and Results Act

HGP – Human Genome Project

INS – Immigration and Naturalization Service

JCSG – Joint Center for Structure Genomics

MBL – Marine Biology Laboratory

NACA – National Advisory Committee for Aeronautics

OES – Office of Experiment Stations

Copyright © 2003 National Academy of Sciences. All rights reserved.

OSHA – Occupational Safety and Health Administration

RAID – Rapid Access to Intervention Development

SBIR – Small Business Innovation Research

TIGR – The Institute for Genomic Research

UIP – Unconventional Innovations Program

VA – Department of Veterans Affairs

WHI – Women’s Health Initiative

Copyright © 2003 National Academy of Sciences. All rights reserved.

Copyright © 2003 National Academy of Sciences. All rights reserved.

2 DEFINING “LARGE-SCALE SCIENCE” IN BIOMEDICAL

3 MODELS OF LARGE-SCALE SCIENCE 29

Chemical Carcinogenesis Program, 43

4 FUNDING FOR LARGE-SCALE SCIENCE 80

5 ORGANIZATION AND MANAGEMENT OF LARGE-

Copyright © 2003 National Academy of Sciences. All rights reserved.

Assessment of Federally Funded Laboratories, 131