Large-scale Biomedical Science pdf

Large-Scale Biomedical Science: Exploring Strategies for Future Research Sharyl J.. Stillman, Editors, Committee on Large-Scale Science and Cancer Research, National Research Council T

ISBN: 978-0-309-50699-1, 296 pages, 6 x 9, (2003)

This executive summary plus thousands more available at www.nap.edu.

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 Research Council

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The nature of biomedical research has been evolving in recent years Technological advances that make it easier to study the vast complexity of biological systems have led to the initiation of projects with a larger scale and scope In many cases, these large-scale analyses may be the most efficient and effective way to extract functional information from complex biological systems

Large-Scale Biomedical Science: Exploring Strategies for Research looks at the role of these new large-scale projects in the biomedical sciences Though written by the National Academies’ Cancer Policy Board, this book addresses implications of large-scale science extending far beyond cancer research It also identifies obstacles to the implementation of these projects, and makes recommendations to improve the process.The ultimate goal of biomedical research is to advance knowledge and provide useful innovations to society Determining the best and most efficient method for accomplishing that goal, however, is a continuing and evolving challenge The recommendations presented in Large-Scale Biomedical Science are intended to facilitate a more open, inclusive, and accountable approach to large-scale biomedical research, which in turn will maximize progress in understanding and controlling human disease

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The nature of biomedical research has been evolving in recent years.

Relatively small projects initiated by single investigators have ditionally been and continue to be the mainstay of cancer research,

tra-as well tra-as biomedical research in other fields Recently, however, 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 andscope (Figure ES-1) For instance, a new approach to biological experi-mentation known as “discovery science” first aims to develop a detailedinventory of genes, proteins, and metabolites in a particular cell type ortissue as a key information source But even that information is not suffi-cient to understand the cell’s complexity, so the ultimate goal of suchresearch is to identify and characterize the elaborate networks of geneand protein interactions in the entire system that contribute to disease.This concept of systems biology is based on the premise that a disease can

techno-be fully comprehended only when its cause is understood from the lecular to the organismal level For example, rather than focusing on singleaberrant 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 effectiveway to extract functional information and interactions from such complexbiological systems

mo-The Human Genome Project is the biggest and best-known scale biomedical research project undertaken to date Another project ofthat size is not likely to be launched in the near future, but many other

large-Executive Summary

projects that fall somewhere between the Human Genome Project and thetraditional small projects have already been initiated, and many morehave been contemplated Indeed, the director of the National Institutes ofHealth (NIH) recently presented to his advisory council a “road map” forthe agency’s future that includes a greater emphasis on “revolutionarymethods of research” focused on scientific questions too complex to beaddressed by the single-investigator scientific approach He noted thatthe NIH grant process will need to be adapted to accommodate this newlarge-scale approach to scientific investigation, which may conflict withtraditional paradigms for proposing, funding, and managing scienceprojects that were designed for smaller-scale, hypothesis-driven research.

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.

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,

investigator-initiated (R01) grants → Often funded through solicited cooperative

agreements More discipline-oriented → Often interdisciplinary

Takes advantage of infrastructure and

technologies generated by large-scale projects → Develops scientific research capacity,

infrastructure, and technologies May or may not involve bioinformatics → Data and outcome analysis highly

dependent on bioinformatics

The recent interest in adopting large-scale research methods has erated many questions, then, as to how such research in the biomedicalsciences should be financed and conducted Accordingly, the NationalCancer Policy Board determined that a careful examination of these issueswas warranted at this time The purpose of this study was to (1) define theconcept of “large-scale science” with respect to cancer research; (2) iden-tify examples of ongoing large-scale projects to determine the currentstate of the field; (3) identify obstacles to the implementation of large-scale projects in biomedical research; and (4) make recommendations forimproving the process for conducting large-scale biomedical scienceprojects, should such projects be undertaken in the future.

gen-Although the initial intent of this study was to examine large-scalecancer research, it quickly became clear that issues pertaining to large-scale science projects have broad implications that cut across all sectorsand fields of biomedical research Large-scale endeavors in the biomedi-cal sciences often involve multiple disciplines and contribute to manyfields and specialties The Human Genome Project is a classic example ofthis concept, in that its products can benefit all fields of biology andbiomedicine The same is likely to be true for many other large-scaleprojects 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 inone field could potentially impact progress as well as funding in otherfields Thus, while this report emphasizes examples from cancer researchwhenever feasible, the committee’s recommendations are generally notspecific to the National Cancer Institute (NCI) or to the field of cancerresearch; rather, they are directed toward the biomedical research com-munity as a whole Indeed, it is the committee’s belief that all fields ofbiomedical research, including cancer research, could benefit from imple-mentation of the recommendations presented herein

Ideally, large-scale and small-scale research should complement eachother and work synergistically to advance the field of biomedical research

in the long term For example, many large-scale projects generate eses that can then be tested in smaller research projects However, thenew 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 planningand oversight These challenges raise the question of how the large-scaleapproach to biomedical research could be improved if such projects are to

hypoth-be undertaken in the future The committee concluded that such ment could be achieved by adopting the seven recommendations pre-sented here to address these issues

improve-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 wayspecific projects are subsequently selected, funded, launched, and evalu-ated (Table ES-1) Although the procedures of NIH and other federalagencies have a degree of flexibility that has allowed some large-scaleresearch endeavors to be undertaken, a mechanism is needed throughwhich input from innovators in research can be routinely collected andincorporated into the institutional decisionmaking processes Also needed

is a more standard mechanism for vetting various proposals for scale projects For example, none of the large projects initiated by NCI todate has been evaluated in a systematic manner There is also a need forgreater planning and oversight by federal sponsors during both the ini-tiation and phase-out of a large-scale project Careful assessment of pastand current large-scale projects to identify best practices and determinewhether the large-scale approach adds value to the traditional models

large-of research would also provide highly useful information for future deavors

en-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 andevaluating proposals from individuals or small groups as well

as from large groups, but in either case, broad consultationwithin the relevant scientific community should occur beforefunding 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 theNIH 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 havebeen selected by the director’s panel, appropriate guidelines forpeer review of specific project proposals should be established.These guidelines should be applied by the institutions that overseethe projects

• Collaborations among institutes could encourage participation bysmaller institutes that may not have the resources to launch theirown large-scale projects.

• NIH should continue to explore alternative funding mechanismsfor large-scale endeavors, perhaps including approaches similar tothose used by NCI’s Unconventional Innovations Program, as well

as funding collaborations with industry and other federal fundingagencies

TABLE ES-1 Summary of the Challenges Associated with Large-ScaleBiomedical Research Projects, and the Committee’s Recommendations

to Overcome These Difficulties

Difficulties Associated with

Develop an NIH-wide mechanism for soliciting and reviewing proposals for large-scale projects, with input from all relevant sectors of biomedical science Clear but flexible plans for entry into and phase out from projects should be developed before funding is provided.

NCI and NIH should commission a thorough analysis of their recent large- 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.

Institutions should develop new ways

to recognize and reward scientific laborations and team-building efforts NIH should provide funding to preserve and distribute reagents and other research tools once they have been created.

col-NIH should examine systematically the impact of licensing strategies and should promote licensing practices that facilitate broad access to research tools Consideration should be given to pursuing projects initiated by academic scientists in cooperation with industry

to achieve large-scale research goals.

No systematic method for assessing

large-scale biomedical research

opportunities exists.

Carefully planning and orchestrating

the launch as well as the phase out of a

large-scale project is difficult, but

imperative for its long term success

and efficiency.

There are very few precedents to guide

the planning and oversight of

large-scale endeavors in biomedical science.

It is difficult to recruit and retain

quali-fied scientific managers and staff for

large-scale projects.

It can be costly and difficult for

investi-gators to maintain reagents produced

through large-scale projects and to share

them with the research community.

Licensing strategies can affect the

availability of research tools produced

by and used for large-scale research

projects.

A seamless transition between

discovery and clinical application is

lacking.

• International collaborations should be encouraged, but an proach for achieving such cooperation should be determined

ap-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 monitorand assess its progress regularly against well-defined milestones

• Carefully planning and orchestrating the launch of a large-scaleproject is imperative for its long-term success and efficiency

• NIH should be very cautious about establishing permanent structures, such as centers or institutes, to undertake large-scaleprojects, in order to avoid the accumulation of additional Institutesvia this mechanism

infra-• Historically, NIH has not had a good mechanism for phasing outestablished research programs, but large-scale projects should notbecome institutionalized by default simply because of their size

• If national centers with short-term missions are to be established, thisshould be done with a clear understanding that they are temporaryand 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 technicaland scientific output (such as data and research tools) of large-scale projects The assessment should include an evaluation ofwhether the field has benefited from such a project in terms ofincreased speed of discoveries and their application or a reduc-tion in costs

• The assessment should be undertaken by external, independentpeer review panels with relevant expertise that include academic,government, and industry scientists

• To help guide future large-scale projects, the assessment shouldpay particular attention to a project’s management and organiza-

tional structure, including how scientific and program managersand staff were selected, trained, and retained and how well theyperformed.

• The assessment should include tracking of any trainees involved in

a project (graduate students and postdoctoral scientists) to mine the value of the training environment and the impact oncareer trajectories

deter-• The assessment should examine the impact of industry contracts orcollaborations within large-scale research projects Industry hasmany potential strengths to offer such projects, including efficiencyand effective project management and staffing, but intellectualproperty issues represent a potential barrier to such collaborations.Thus, some balance must be sought between providing incentivesfor producing the data and facilitating the research community’saccess to the resultant data

– In pursuing large-scale projects with industry, NIH should fully consider the data dissemination goals of the endeavor be-fore making the funds available

care-– To the extent appropriate, NIH should mandate timely and restricted release of data within the terms of the grant or con-tract, in the same spirit as the Bermuda rules adopted for therelease of data in the Human Genome Project

un-The committee has formulated four additional recommendationsaimed at improving the conduct of possible future large-scale projects.These recommendations emerged from the committee’s identification ofvarious potential obstacles to conducting a large-scale research projectsuccessfully and efficiently To begin with, human resources are key tothe success of any large-scale project If large-scale projects are deemedworthy of substantial sums of federal support, they also clearly warrantthe highest-caliber staff to perform and oversee the work But if qualifiedindividuals, especially at the doctoral level, are expected to participate insuch undertakings, they must have sufficient incentives to take on therisks and responsibilities involved In particular, effective administrativemanagement and committed scientific leadership are crucial for meetingexpected milestones on schedule and within budget; thus the success of alarge-scale project is greatly dependent upon the skills and knowledge ofthe scientists and administrators who manage it, including those withinthe federal funding agencies However, it may be quite difficult to recruitstaff with the skills to meet this need because of the unusual status of suchmanagerial positions within the scientific career structure, and becausescientists 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, thecommittee concluded that both universities and government agenciesneed 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 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.

in-• Funding agencies should develop appropriate career paths for viduals who serve as program managers for the large-scale projectsthey fund

indi-• 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 structive models in achieving these goals, as they have a history

in-of rewarding scientists for their participation in team-orientedresearch

• It is important to establish guiding principles for such issues asequitable 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 adequatefunding to universities engaged in large-scale biomedical researchprojects so that these individuals can be sufficiently compensatedfor their role and contribution

• Universities, especially those engaged in large-scale research,should develop training programs for scientists involved in suchprojects Examples include courses dealing with such topics asmanaging teams of people and working toward milestones withintimelines Input from industry experts who deal routinely withthese issues would be highly valuable

The committee also identified potential impediments to deriving thegreatest benefits from the products of large-scale endeavors in terms ofscientific progress for biomedical research in general Large-scale projectsare most likely to speed the progress of biomedical research as a wholewhen their products are made widely available to the broad scientificcommunity However, concerns have been raised in recent years aboutthe willingness and ability of scientists and their institutions to sharedata, reagents, and other tools derived from their research Since a pri-

mary goal of many large-scale biomedical research projects is to producedata and research tools, NIH should facilitate the sharing of data and thedistribution 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 forlarge-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, establishedthrough 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 reagentsand tools would improve the quality of the data obtained throughresearch and make it easier to compare data from different investi-gators

• Producing the reagents and making them widely available to manyresearchers would be more cost-effective than providing funds to afew scientists to produce their own

An issue closely related to the sharing of data and reagents is thelicensing 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 Innovationsthat can be used as research tools may offer the greatest challenge in thisregard because it is difficult to predict the future applications and value

of a particular tool, and because a number of different tools may be neededfor a single research project Since many large-scale projects in the bio-sciences aim to produce data and other tools for future research, thissubject is especially salient for large-scale research The committee con-cluded that NIH should continue to promote the broad accessibility ofresearch tools derived from federally funded large-scale research to theextent feasible, while at the same time considering the appropriate rolefor intellectual property rights in a given project However, in the absence

of adequate information and scholarly assessment, it is difficult to mine how NIH could best accomplish that goal Thus, the committeerecommends that such an assessment be undertaken, and that appropri-ate actions be taken based on the findings of the study

deter-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 medical research projects.

bio-• Whenever possible, NIH and NCI should use their leverage andresources to promote the free and open exchange of scientificknowledge and information, and to help minimize the time andexpense of technology transfer

• Depending on the findings of the proposed study, NIH shouldpromote licensing practices that facilitate broad access to researchtools by issuing licensing guidelines for NIH-funded discoveries

In addition to the role of federal funding agencies, the committeeconsidered the role of industry and philanthropies in conducting large-scale biomedical research Public–private collaborations provide a way toshare the costs and risks of innovative research, as well as the benefits.Philanthropies and other nonprofit organizations can play an importantrole in launching nontraditional projects that do not fit well with federalfunding mechanisms Pharmaceutical and biotechnology companies alsomake enormous contributions to biomedical research worldwide Tradi-tionally, the role of independent companies has been to pursue appliedresearch aimed at producing an end product; however, the distinctionbetween “applied” and “basic” research has blurred in recent years, inpart 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 usefulpractices, has further obscured the distinction

Several recent projects initiated and funded by industry or carriedout in cooperation with industry and nonprofit organizations clearlydemonstrate the potential value of contributions by these entities tolarge-scale research endeavors The Single Nucleotide Polymorphism,

or SNP, consortium is a prime example of how effective these sectorscan be when involved in a large-scale research projects Industry inparticular has many inherent strengths that could be brought to bear onlarge-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 couldoptimize the pace of biomedical research and development, potentiallyleading to more rapid improvements in human health Thus, the com-mittee recommends that cooperation between academia and industry beencouraged for large-scale research projects whenever feasible

Recommendation 7: Given the changing nature of biomedical search, consideration should be given to pursuing projects initiated

re-by academic scientists in cooperation with industry to achieve the

goals of large-scale research When feasible, such cooperative 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.

ef-• 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 ors could greatly facilitate translational research and thus speedclinical applications of new discoveries

endeav-Great strides in biomedical research have been made in recent 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 thistraditional approach to experimentation Recent large-scale collaborationshave also allowed scientists to tackle complex research questions thatcould not readily be addressed by a single investigator or institution Thecurrent leadership of NIH and many scientists in the field clearly haveexpressed an interest in integrating the discovery approach to biomedicalscience with hypothesis-driven experimentation As a result, at least somelarge-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 learnfrom when planning and launching a new large-scale project Moreover,there has been little formal or scholarly assessment of large-scale projectsalready undertaken

de-Now is the time to address the critical issues identified in this report

in order to optimize future investments in large-scale endeavors, ever they may be The ultimate goal of biomedical research, both large-and small-scale, is to advance knowledge and provide society with usefulinnovations 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-scalebiomedical research, and help strike the appropriate balance betweenlarge- and small-scale research to maximize progress in understandingand controlling human disease

what-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

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 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.

pre-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.

For more information about the Institute of Medicine, visit the IOM home page at: www iom.edu.

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