Large-Scale Biomedical Science Exploring Strategies for Future Research (2003) / Chapter Skim
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3. Models of Large-Scale Science
3. Models of Large-Scale Science
Pages 29-79
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From page 29... ...
, 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 research.
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From page 30... ...
30 LARGE-SCALE BIOMEDICAL SCIENCE initiative by a fonder, however, individual scientists may find it very difficult to obtain the funding necessary to launch an expensive, longterm, large-scale project because of the nature of traditional funding mechanisms (see Chapter 4~. Another common thread among these projects is their dependence on new or developing technologies.
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From page 31... ...
As technological advances were made, however,1 some molecular biologists began to discuss the feasibility and potential value of mapping and sequencing the entire human genome (see Figure 3-1~. The first editorial published in a major scientific journal advocating a large-scale approach to sequence the human genome brought the concept to the scientific mainstream, with an emphasis on cancer research (Dulbecco, 1986~.
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From page 32... ...
1991 -- NIH funds ~175 genome projects, with an average grant size of ~$300,000/year. July 1991 -- Craig Venter, then at NIH, reveals that NIH has applied for patents on expressed sequence tags (ESTs)
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From page 33... ...
DeLisi, formerly chief of mathematical biology at NIH, had been exploring the feasibility of such a project, and in 1986 he proposed a plan for a 5-year DOE HGP that would comprise physical mapping, development of automated high-speed sequencing, and research into computer analysis of sequence data. Soon after, in May 1986, a meeting on molecular biology hosted by lames Watson at Cold Spring Harbor included a special session dedicated to discussing the possibility of an HGP.
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From page 34... ...
, a key player in developing the genetic linkage map of the human genome, was founded by Nobelist lean Dausset with funds from a scientific award and gifts from a private French donor. Through additional support from the Howard Hughes Medical Institute (HHMI)
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From page 35... ...
For example, in 1991 NIH funded about 175 different genome projects, with an average grant size of $312,000 a year (about 1.5 times the average grant size for basic research, and about equal to the average AIDS research grant)
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From page 36... ...
This drop caused great consternation among biomedical scientists, and many assumed that it was due directly to the transfer of funds to the HGP, though close examination of concurrent changes in NIH funding patterns suggests that this was not the case. In the mid-1980s, the average grant period was extended from 3.3 to 4.3 years to provide greater stability for funded projects and reduce the frequency of grant applications; the average amount of funding per grant also increased significantly.
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From page 37... ...
In 1998, the technology of DNA sequencing took a major step forward when the Applied Biosystems Incorporated (ABI) PRISM 3700 entered the laboratory market (Davies, 2001; Wade, 2001~.
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From page 38... ...
than traditional sequencing methods (Davies, 2001~. The new sequencing machines were used early on by Craig Venter, who had left NIH in 1992 to found The Institute for Genomic Research (TIGR)
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From page 39... ...
Celera still planned to release raw sequence data free of charge, but only every 3 months, as opposed to every 24 hours as in the public project (Davies, 2001~. Shortly after the launch of Celera, the Wellcome Trust doubled support for the Sanger Center, Great Britain's main sequencing center in the public effort.
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From page 40... ...
PAST EXAMPLES OF LARGE-SCALE PROJECTS FUNDED BY NCI Three large-scale programs developed by NCI in the 1950s and 1960s while perhaps not strictly meeting the working definition of large-scale science used for this report, may prove instructive in understanding some of the issues relevant to NCI's more recent large-scale initiatives. Although NCI's extramural grants program, like those of most branches of NIH, has supported mostly investigator-initiated projects funded on the basis of scientific peer review, a markedly different approach was used for much of the research carried out under these three programs in Cancer Chemotherapy, Chemical Carcinogenesis, and Cancer Viruses.
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From page 41... ...
The program was widely criticized for its dependence on contract research and its lack of communication with the scientific community. Indeed, a 1965 White House report, commissioned to determine whether Americans were getting their money's worth from NIH-sponsored medical research, singled out the cancer chemotherapy program for harsh criticism.
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From page 42... ...
Another independent committee was appointed by the secretary of Health, Education and Welfare in 1966 to review the funding of NIH research, including the cancer chemotherapy program. Chaired by lack Ruina, who had extensive experience with grant and contract support of research and development in the Department of Defense, the committee concluded that the grant mechanism was inappropriate for directed research and development programs, and that contracts should be used instead.
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From page 43... ...
Of the three NCI programs discussed here, chemical carcinogenesis received the least amount of funding and attention, and was not remarkably productive. The criteria for determining whether a given chemical is carcinogenic were (and still are)
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From page 44... ...
This basic research is supported by grants, and there are currently no large-scale projects. Cancer Virus Program NCI's third major contract program, the special virus cancer program, was established in 1964.
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The cancer virus program could be considered a significant failure of directed research since it did not lead directly to the identification of any viruses that cause human cancer; however, it had many indirect, beneficial effects on the scientific community. Many viruses (mostly RNA viruses)
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From page 46... ...
· The Mouse Tumor Gene Index identifies genes expressed during the development of mouse tumors. The goals of CGAP clearly overlap extensively with some of the goals of the HOP (for example, identifying expressed genes and using experimental high-throughput technologies)
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From page 47... ...
In an attempt to bridge the gap between laboratory advances and the clinical adoption of biomarkers, EDRN has brought organizations with varied interests and corporate cultures together in a single scientific consortium.~° Because many steps are necessary to ensure that a marker is accurate, reproducible, and practical for medical application, the consortium is organized into four working and two oversight components. The working components are as follows: · Biomarker Developmental Laboratories that identify, characterize, and refine techniques for finding molecular, genetic, and biologic signs of cancer · Clinical and Epidemiological Centers that focus on providing the network with blood, tissue, other biological samples, and medical information on families with histories of cancer · Biomarker Validation Laboratories that standardize tests and prepare them for clinical trials, serving as crucial intermediaries between the Biomarker Developmental Laboratories and clinical practice 9 See |
From page 48... ...
This committee determines which markers identified by the Biomarker Developmental Laboratories should advance to the Biomarker Validation Laboratories. Its members are principal investigators from the funded laboratories and centers, NCI program staff, and other ad hoc members invited by the committee.
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The UIP clearly differs from the core scientific programs at NIH in 13 Carol Dahl, former director of the NCI's Unconventional Innovations Program, in a presentation to the National Cancer Policy Board, July 16, 2002. 14 See |
From page 50... ...
Mouse Models of Human Cancers Consortium The Mouse Models of Human Cancers Consortium (MMHCC) , assembled from multidisciplinary teams of scientists, was established in 1999 for the collaborative development, characterization, and validation of mouse models that parallel the ways in which human cancers develop, 15 "This program seeks to stimulate development of radically new technologies in cancer care that can transform what is now impossible into the realm of the possible for detecting, diagnosing, and intervening in cancer at its earliest stages of development." See |
From page 51... ...
NCI works with the consortium to organize workshops and symposia, to provide information about the models and related technology, and to plan for distribution of the validated mouse models to the cancer research community. Funding for members of the MMHCC is available through both NIH intramural projects and the U01 funding mechanism (see Chapter 4 for an explanation of the various NIH funding mechanisms)
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From page 52... ...
The Consortium was officially launched when 19 groups of investigators from more than 30 institutions were provided with MMHCC funding to develop and evaluate mouse models for cancers of eight major organ systems breast, prostate, lung, ovary, skin, blood and lymph system, colon, and brain.l8 The Consortium has since grown into an international collaboration involving more than 70 institutions. Specialized Programs of Research Excellence In 1992, NCI established the Specialized Programs of Research Excellence (SPOREs~l9 to promote interdisciplinary research through a special $20 million appropriation from Congress.
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From page 53... ...
The goal of this laboratory is to develop research tools, such as protein arrays, and to synthesize thousands of small molecules and screen them for their biological effects (ScienceScope, 2002~. Small molecules identified in such screens can provide versatile research tools for the study of protein function (reviewed by Stockwell, 2000)
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From page 54... ...
Support for new individual research projects was not the intent of these large-scale project awards; rather, a signifi20 See |
From page 55... ...
AFCS investigators work in core laboratories located at several different academic centers, including the California Institute of Technology in Pasadena; the San Francisco Veterans Administration Medical Center; Stanford University; the University of California, San Diego; and University of Texas Southwestern. Two biotechnology companies will also participate in AFCS studies by providing custom-made materials, such as antisense reagents (ISIS Pharmaceuticals of Carlsbad, California)
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From page 56... ...
They include Eli Lilly and Company, Johnson and Johnson, the Merck Genome Research Institute, Novartis Pharmaceuticals Corporation, Chiron Therapeutics, Aventis, and the Agouron Institute. In the fall of 2001, NIGMS announced the provision of $8 million for a second glue grant to the Cell Migration Consortium.
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From page 57... ...
In addition to the principal investigator and participating investigators, other essential components of a large-scale collaborative project include a steering committee, an external advisory committee, and a program director. The steering committee is largely responsible for governance of the project and plays a major role in developing goals and operating procedures.
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From page 58... ...
The Institute anticipates spending a total of around $150 million on these projects over 5 years. The projects at the research centers are intended to serve as pilots leading to subsequent large-scale research networks in structural genomics.
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From page 59... ...
There is also much interest among pharmaceutical and biotechnology companies in pursuing structural genomics projects (Smaglik, 2000, Service, 2001a-c)
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From page 60... ...
The results of the structural genomics projects are meant to be freely available for use by the entire research community, and therefore must be deposited promptly,30 prior to publication, in the Protein Data Bank (PDB) , 30 According to the NIGMS Statement on Coordinate Deposition for Structural Genomics, an international agreement called for releasing structure information on most proteins soon after completion, but setting aside some structures for a limited period of time (less than 6 months)
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From page 61... ...
The Pathogen Functional Genomics Resource Center The National Institute of Allergy and Infectious Diseases (NIAID) recently established a centralized facility providing the research community with resources for conducting functional genomics research on human pathogens and invertebrate vectors.3~ NIAID awarded a 5-year, $25 million contract to TIGR to establish the Pathogen Functional Genomics Resource Center (PFGRC)
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From page 62... ...
Participants will be followed for 8 to 12 years. The WHI consists of three studies: · A clinical trial that tests the effects of three different prevention approaches HRT, diet modification, and calcium and vitamin D supplementation on heart disease, cancer risk, and osteoporosis.
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From page 63... ...
(in millions of dollars) Clinical Coordinating Center 11.7 175.5 40 Clinical Centers 35.3 530.0 Total 47.0 705.5 Clinical Trial by Component Calcium, Vitamin D 1.2 18.2 Hormone Replacement Therapy 15.5 232.4 Dietary Modification 27.7 415.1 Observational Study 2.6 39.8 Total 47.0 705.5 Average Cost Total Cost Clinical and Observational Study Number per Year All Years Cost per Participant Enrolled (in dollars)
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From page 64... ...
The Fred Hutchinson Cancer Research Center in Seattle, Washington, serves as the WHI Clinical Coordinating Center for data collection, management, and analysis. The WHI is a large-scale-science project not so much because it is employing high technology to discover biological processes, but more because of its size and collaborative nature.
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From page 65... ...
The center focuses primarily on the preclinical and early clinical stages of vaccine development, but works closely with the HIV Vaccine Trials Network, which conducts all phases of clinical trials. A novel venture within the NIH intramural research program, the VRC receives joint funding from NIAID and NCI and is spearheaded by NIAID, NCI, and the NIH Office of AIDS Research.
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From page 66... ...
The goals of the STC Program are to enable academic research teams to: · Exploit opportunities in science and engineering in which the complexity of the research problems or the resources needed to solve them require the advantages of collaborative relationships that can best be provided by campus-based research centers. · Involve students, research scientists, and engineers in partnerships to enhance the training and employability of professionals through an awareness of potential applications for scientific discoveries.
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From page 67... ...
Two other independent reviews at about the same time came to similarly positive conclusions, and also resulted in recommendations for improving administration and oversight of the program (NAPA, 1995; ABT Associates, 1996~. THE SNP CONSORTIUM Single nucleotide polymorphisms, or SNPs, are common, small variations that occur in human DNA throughout the genome.
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From page 68... ...
These discussions led to the establishment of the SNP Consortium in 1999. The SNP Consortium38 is a nonprofit entity comprising the Wellcome Trust and a group of pharmaceutical and technical companies.39 Its mission is to identify SNPs distributed evenly throughout the human genome and to make information on these SNPs available to the public without intellectual property restrictions.
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From page 69... ...
Scientists realized only recently that a haplotype map might be feasible when they discovered that relatively large blocks of DNA are inherited in this way. Computer simulations predicted that DNA haplotypes 40 This collaborative effort was funded by the National Human Genome Research Institute and the SNP Consortium.
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From page 70... ...
The work will be done by several biotechnology companies and public laboratories, including the Sanger Center and the Whitehead Institute, but decisions are still pending on such issues as how data collection will be standardized, how the map will be structured, and how the work will be divided. It is hoped that the new map will provide an invaluable tool to simplify the search for associations between DNA variations and complex diseases such as cancer, diabetes, and mental illness.
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From page 71... ...
But many others question the sensitivity and specificity of current mass spectrometers, suggesting that such an undertaking would be premature, and that it would be more useful to fund individual investigators to study small parts of large, complex protein networks (Check, 2002~. HOWARD HUGHES MEDICAL INSTITUTE The Howard Hughes Medical Institute (HHMI)
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From page 72... ...
This new 10-year, $500 million project44 may be viewed as another form of large-scale science funded by a nonprofit organization. HHMI plans to build a permanent biomedical research center that will develop advanced technology for biomedical scientists and provide a collaborative setting for the development of new research tools.
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From page 73... ...
. Investigators are likely to include computational scientists, chemists, physicists, engineers, and biomedical scientists with cross-disciplinary expertise.
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From page 74... ...
NCI is particularly interested in how the synchrotron facilities will advance the study of cancer-related molecules, because an understanding of detailed protein structure will help cancer researchers develop targeted drug therapies. NIGMS and NCI anticipate that information about molecular structures will allow scientists to help develop new medicines and diagnostic techniques.
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From page 75... ...
However, some of this work could potentially have broader implications for biological research, such as novel approaches for DNA sequencing (Alper, 1999) or sophisticated biosensors.
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From page 76... ...
Under the leadership of NCI director Richard Klausner, NCI has even launched a pilot program modeled in part after DARPA, as well as other agencies, such as NASA.
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From page 77... ...
The DARPA model works best when the manager is an intellectual peer of the scientists being funded. But for biomedical scientists, a 4-year absence from the laboratory and the resultant lack of published scientific papers during that period could very well be disastrous from a long-range career perspective.
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From page 78... ...
Most projects to date have adopted a policy of making data publicly available, at least in raw form. Research tools and reagents generated through large-scale projects funded by NIH are also often made available to other scientists at cost, but doing so requires a considerable commitment of NIH resources and infrastructure support.
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From page 79... ...
MODELS OF EUGENE SINE 79 clude scientists not directly involved with the protect assess progress and provide advice on future direchons. It is sUll too early to determine how e~ecUve these mechanisms are' but Bus far they appear to be acceptable to the scientific community.
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