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George Curlin, M.D.
Acting Director, DMID
Dr. George Curlin, Acting Director of the Division of Microbiology and Infectious Diseases (DMID), welcomed the Microbiology and Infectious Diseases Subcommittee of the National Advisory Allergy and Infectious Diseases Council and provided a brief report of Division activities. He thanked the ad hoc Subcommittee members Drs. John Mekalanos and Gary Schoolnik, and welcomed other participants who were invited to discuss agenda items with the Subcommittee. In particular, a number of individuals were invited to participate in the pathogen genome sequencing discussion, which the majority of this Subcommittee meeting was devoted to. He also noted personnel and organizational changes since the last meeting, including Dr. Stephanie James’ appointment as the Division’s Acting Deputy Director, and the addition of Dr. Jon Daugherty, a microbiologist who has joined the Clinical and Regulatory Affairs Branch.
Dr. Curlin briefly summarized recent program events, including a meeting with our U.S. Japan Cooperative Medical Science Program colleagues in Japan on emerging and re-emerging infectious diseases and a NIH State-of-the-Art meeting on chronic fatigue syndrome in adolescents. Dr. Curlin also noted two upcoming DMID meetings, one on Staphylococcus aureus and one on community acquired pneumonia.
Dr. Curlin then presented one of two concepts to be presented to the Subcommittee for clearance: INDO-US Vaccine Action Program (VAP) Starr Grants. This initiative seeks to continue and expand the INDO-US Vaccine Action Program (VAP) using funds provided for this program to the NIAID Restricted Gift Fund by the Starr Foundation. The goal of the initiative is to bring together relevant biomedical knowledge and technology to develop new vaccines and immunodiagnostic reagents for the prevention and detection of infectious diseases of importance to India. The Subcommittee approved the concept.
The remainder of the Subcommittee meeting was devoted to a discussion on pathogen genome sequencing. Dr. Michael Gottlieb, DMID’s Parasite Drug Development Program Officer, introduced the session, which entailed a number of presentations and discussions on the impact of genomics on infectious disease research and on the opportunities presented by expanding NIAID support in this area. The session brought together scientists engaged in various aspects of genomic research including sequencers and information specialists as well as those involved in mining the genetic information for drugs and vaccines and for understanding the molecular basis of pathogenesis. The session’s purpose was to:
- Update Council on microbial genomic research, especially NIAID supported activities.
- Identify issues and areas that would benefit from NIAID’s leadership and support.
- Present a Concept for Clearance. The Concept is designed to support additional pathogen sequencing and post- genomic facilities for exploiting genome sequence data.
Scientific Highlights of this Exciting Session Included:
- New sequencing technology: Dr Claire Fraser (TIGR) described the latest high-capacity sequencing technology, Applied Biosystems’ 3700 DNA Analyzers, which run 24 hours per day unattended with an output of just under 1000 sequencing reads per day. This will increase the speed and efficiency of genome sequencing by at least five-fold, potentially revolutionizing the field. Dr. Fraser also summarized some of the most important lessons learned from previous microbial genome sequencing projects: 1) novel insights into genome organization, such as the discovery that Borrelia burgdorferi has an unexpectedly large number of circular and linear plasmids in addition to its large linear chromosome; 2) each organism is unique in significant ways, i.e. 20-40% of each organism’s open reading frames are not homologous with sequences in existing databases; 3) evolution and phylogeny must be considered on a whole genome rather than single gene basis; 4) the importance of continually updating genome sequence annotations as new sequences are added to databases; and, 5) the power of using microarray approaches for functional genomics.
- Identification of genes of interest:
Pathogenesis - Dr. Fred Blattner (U. of Wisconsin) described existing and potential technologies for comparative sequencing of closely related species, for example determining the sequence of E. coli O157 based on comparisons with the complete sequence of E. coli K12. This approach, when feasible, represents marked savings in time and expense. The comparison of genomes from pathogenic and nonpathogenic strains can provide direct leads to pathogenic determinants. Dr. Blattner and colleagues with infectious disease expertise are pursuing this comparative approach for sequencing a number of other enteropathogens and related organisms. He will use the three complementary technologies of comparative genome assembly (scanning for major interruptions, additions and rearrangements), splicing out and characterizing large pathogenicity islands, and optical mapping (invented by David Schwartz of NYU). The latter approach rapidly generates restriction maps by microscopy thereby greatly facilitating assemblies of contiguous sequences and comparisons between isolates.
Drug targets - Dr. Gary Schoolnik (Stanford U.) discussed using cDNA microarrays to study host-pathogen relationships, for example during the establishment of "latency" by Mycobacterium tuberculosis, and described creation and use of a M. tuberculosis cDNA array for antibiotic discovery. Dr. Schoolnik is also using this array to compare a pathogenic M. tuberculosis genome to the avirulent M. bovis BCG genome, in order to identify potential virulence determinants for vaccine development, and is collaborating with Affymetrix to develop a high density oligo "chip" for M. tuberculosis.
Host response to infection - Dr. Ed Mocarski (Stanford U.) described the power of "array" technologies for comprehensive gene expression analysis of complex genomes and for analyzing regulation of gene expression within host cells during viral infection.
- Making sequence information accessible: Dr. George Weinstock (U. of Texas) described progress in the Treponema pallidum genome sequence project. Sequencing this pathogen has been extremely important because T. pallidum cannot be cultured in the laboratory; thus, understanding the biology of this organism and the pathogenesis of syphilis has lagged considerably until now. The fully assembled and annotated sequence information is now publicly available to all investigators. Dr. Tom Brettin (Los Alamos National Laboratories), who works with STD researchers on database development, described the importance of the bioinformatics and relational databases that must bring together and optimize the utility of results from genome sequencing projects and whole genome functional analyses. Computational tools facilitate comparisons among pathogen sequences and whole genomes and make functional predictions that may be tested experimentally.
- New partnerships: Dr. Thomas Caskey (Merck Research Laboratories and Merck Genome Research Institute) described genome sequence as "the driver of virtually everything we do". He detailed how Merck is now using "chips" to identify new drug and vaccine targets as well as to perform drug metabolism and safety studies. Dr. Caskey expressed the views that genes should be considered research tools, "widely available and not tightly held"; and that NIAID’s support of the sequencing effort is providing "an enabling backbone of knowledge which is freely accessible to individuals so that they can use their creativity in the discovery process". While not giving a presentation, Dr. Celia Caulcott, Programme Manager for Scientific Business Initiatives for the Wellcome Trust, also attended the session and spoke of the need for coordination between NIAID and Trust efforts on pathogen genome sequencing.
The Council members and other session participants were in agreement on the tremendous potential contribution of genomics to our understanding of microbial pathogens and the expected benefits of such research for the control and prevention of infectious diseases. The presentations and discussions raised a number of issues that require further NIAID input and thought. There was consensus that the Division and the Institute must address these issues in order to take full advantage of the opportunities provided by the scientific findings and advances.
At the conclusion of the genome discussion, Dr. Ann Ginsberg, DMID’s Tuberculosis program officer, presented to the Subcommittee a trans-division concept on post genomic research entitled "Whole Genome Approaches to Pathogen Research." This initiative, which would be executed through a contract program, would allow NIAID to promote the use of the growing amount of sequence data becoming available by supporting the development and distribution of technologies and reagents to apply "whole genome" approaches to address relevant microbiology and infectious diseases questions. This concept generated considerable discussion among Subcommittee members and invited participants, particularly the fact that it would be pursued through the contract mechanism. Several participants suggested this proposal be broadened to include grants as well as contracts and DMID staff agreed to take their suggestions into consideration as they further develop the initiative.
Finally, Dr. Leigh Sawyer, Clinical Trials Program Officer, reported on the recent Collaborative Antiviral Study Group annual meeting; Dr. Ginsberg provided an update on the activities of the Advisory Council for the Elimination for Tuberculosis, an advisory body established by the Secretary, DHHS;
Dr. Elizabeth Higgs, International Tropical Disease Research Program Officer, provided highlights of the seventh annual International Centers for Tropical Disease Research meeting held in May, 1998; and
Dr. Steve Heyse, Medical Bacteriology and Antibacterial Resistance Program Officer, reported on the 20th annual Mycoses Study Group meeting.
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