Historically, infectious or communicable diseases have been one of the most fertile areas for biomedical research, and the field provides many examples where basic research has translated into major advances in human health. The past decade has seen a resurgence of public and scientific interest in infectious disease research driven by four key factors:
Identification of numerous emerging pathogens that are the source of significant morbidity and mortality; examples include HIV, Borrelia burgdorferi (Lyme disease), Hantaviruses, Equine Encephalitis, Rotaviruses, etc.
The recent discovery that microbial infections are implicated in diseases heretofore thought to be of physiological origin; for example, Helicobacter pylorii in gastric ulcers and cancer of the stomach or chronic hepatitis B infection in cancer of the liver.
Re-emergence of older pathogens due to drug resistance and/or changing socioeconomic factors; e.g. the rise in the incidence of tuberculosis in urban populations in the US.
Increasing risks from opportunistic infections in aging or immunocompromised patients.
Fortunately, advances in basic biomedical research, particularly molecular biology, are providing clinicians with important tools and approaches to treating communicable diseases, and the translation of new discoveries into clinical practice has proved to be remarkably rapid.
The School of Medicine is well positioned to build an outstanding program in infectious diseases: its program in Lyme disease is internationally recognized and well-funded; it has outstanding basic science programs in the Department of Molecular Genetics & Microbiology; and its clinical and basic science faculty have a broad spectrum of expertise in the molecular biology, molecular pathogenesis, prevention, and treatment of microbial diseases. Furthermore, regional institutions such as Brookhaven National Laboratory (BNL), Cold Spring Harbor Laboratory (CSH), Plum Island Laboratory, and the Picower Institute provide complementary strengths in other areas of infectious disease research, and numerous research collaborations already exist with investigators in these institutions. For better or worse, Long Island's geography and demographics have proved fertile ground for emergence of new pathogens such as B. burgdorferi, Hantavirus (SI 1), Eastern Equine Encephalitis, and Babesia microti, providing the SOM with an unusual opportunity to address local health problems that have national implications.
II. Proposed Programs in Infectious Diseases
A. Program in Emerging Pathogens The Program in Emerging Pathogens is an initiative developed by the Department of Medicine based on its experience and expertise in Lyme disease, Hantaviruses and Toxoplasma gondii. The major goal of the proposed Program is to bring together researchers from different disciplines to address the basic problems of emerging infectious diseases, defined as "diseases of infectious origins whose incidence in humans has increased within the past two decades or threatens to increase in the future". Using advanced techniques in molecular biology, immunology, structural biology and evolutionary biology, the Program in Emerging Pathogens will build on the unique strengths in these fields at SUNYSB and regional research centers (BNL, CSH, Plum Island) to develop a comprehensive approach to the rapid diagnosis, treatment and prevention of emerging pathogens. For example, the Program will take advantage of the expertise in viral and non-viral vectors in various basic science groups at these institutions for developing novel vaccine strategies; it will build on existing collaborations with structural and molecular biologists at BNL to develop a multivalent vaccine for Lyme disease; and it will expand its joint program with BNL in large scale sequencing of nucleic acids from emerging pathogens.
The major focus of research in the Program will be host-microbe interactions, which requires both an understanding of the specific host defenses involved in warding off infection by a specific pathogen and the tactics employed by the microbe to evade these defenses. Thus the program will include projects in molecular pathogenesis, including cloning and expression of microbial surface antigens; molecular immunology to define specific cells and molecules involved in immunological recognition and host defenses; and structural biology, to identify specific epitopes for potential diagnostic and/or vaccine development. In addition, the Program will develop collaborative studies in the ecology and epidemiology of emerging pathogens, using regional expertise in population biology, mathematical modeling and statistics, and evolution. This approach will make it possible to define the 3-dimensional structure, synthesis, and immunological properties of key microbial components; identify a pathogen's genetic and immunological variability in the population and its role in the pathogenesis of disease; and predict its evolutionary dynamics. For example, this group has already begun large scale sequencing of the genomes of B. burgdorferi and Rochalima henselia. Ultimately, these studies should lead to rational development of new therapeutic interventions, including passive and active immunization, as well as cytokine and anti-sense therapies.
Faculty in the Department of Pathology are also working in the area of emerging pathogens and mechanisms involved in infectious disease. These include studies on the identification of genes involved in fungal pathogenicity (virulence), particularly cryptococcus; the ongoing work of Benach and his group on the antigens of borrelia and his recent development of an animal model for a recently-discovered strain of relapsing fever.
Dr. B. Luft is currently Director of the Program in Emerging Pathogens, but due to his administrative duties as Acting Chairman of the Department of Medicine and Chief of the Division of Infectious Diseases, it will be necessary to recruit a Scientist/Administrator with expertise in viral immunopathogenesis to develop the medical virology program and coordinate the day-to-day operations of the Program. In addition, the Program will need to build expertise in cellular immunology by recruiting two junior faculty with research interests in antigen presentation and lymphokine biology. Salary support for two of the three new faculty will come from the Department of Medicine; the Program is requesting matching funds form the SOM in the form of salary support for the third faculty member and start-up funds for the three investigators. In addition, the development of the Program will require a P3 laboratory that could accommodate several pathogens at a time, new animal facilities at P3 and P4 containment levels; these facilities could be planned as part of the Program's allocation in the Center for Molecular Medicine. Discussions have been initiated with the Director of Plum Island Laboratory on the feasibility of using the P4 animal facility at that site.
Research in the Program for Emerging Pathogens will be supported primarily via extramural funding from the NIH, CDC, and WHO. In addition, clinical and translational projects should attract funding from pharmaceutical and biotechnology companies. Where appropriate, the Program also will consider creating private sector ventures that leverage the resources of the Long Island High Technology Incubator, the Center for Biotechnology, and other academic-industry ventures; the presence of these resources will help attract top level scientists to the Program.
The Program in Emerging Pathogens will contribute substantially to the educational programs of the SOM through training of pre- and postdoctoral students and fellows, continuing education of faculty, and public health education of regional health care personnel. The Program also proposes to work with the School of Health Technology and Management in development of a MPH program.
B. Human Immunodeficiency Virus/AIDS Research Program HIV is undoubtedly the best known and most lethal pathogen to emerge in this century, and has been the subject of intense research for a decade. At present, the School of Medicine has several HIV/AIDS research programs which are under the direction of investigators in the Departments of Medicine, Microbiology, Chemistry and Pharmacology. Ongoing studies include the interaction of HIV with macrophages and B-lymphocytes (R. Steigbigel), development of compounds that inhibit key enzymes in viral replication (F. Johnson, T. Bell), structure and assembly of HIV protease and capsid proteins (C. Carter), HIV integrase (Schlepper, Erietto), and the use of in situ PCR techniques to diagnose and to understand the mechanism and spread of HIV on human papilloma virus infections (Nuovo). The Sate-designated HIV Evaluation and Treatment Center evaluates new AIDS therapies with sponsorship from NIH and pharmaceutical industry.
The proposed HIV/AIDS Research Program will continue and expand the ongoing studies in molecular pathogenesis of HIV and in drug design. The research and clinical trials program of the Evaluation and Treatment Center, which has attracted substantial funding from pharmaceutical companies and become an important regional center for experimental AIDS therapy, is seriously constrained by the lack of dedicated space and facilities; thus, development of the General Clinical Research Center and support from the proposed Clinical Pharmacology Program will be critical for its growth. At present, the School of Medicine does not have a integrative program in HIV/AIDS research, although Dr. Steigbigel spearheads several collaborative projects on the molecular pathogenesis of HIV. The drug discovery programs make good use of expertise at SUNYSB, but represent only a small part of the effort of the main investigators. Thus while the program has had good success in fostering interdepartmental collaboration and developing a broad base of industrial support for its clinical research, it has yet to provide the basis for a comprehensive translational research program. Moreover, the lack of "critical mass" and faculty with specific expertise in retroviruses have made it difficult to compete for large collaborative grants.
C. Program for Infectious Diseases
The Program for Infectious Diseases has been founded by the faculty of the Department of Molecular Genetics & Microbiology with the aim of developing a joint initiative among all the relevant Departments of the School of Medicine to serve as an umbrella organization for communicable disease research in the region. Its major goals are to foster individual and joint research programs in both the basic and clinical aspects of infectious diseases and to provide novel educational programs for pre- and postgraduate training of M.D. and Ph.D. students. The proposed membership of the Program for Infectious Diseases will include faculty and investigators from the SOM, SUNY Stony Brook, BNL, CSH and Plum Island. While the Program will, in principle, cover all types of research on infectious agents, it will initially build on existing strengths in characterization of endemic infectious agents, emerging and re-emerging agents, molecular mechanisms of pathogenesis, of Salmonella typhimurarium and hepatitus B virus, prevention and control of infectious diseases, and epidemiology of infectious diseases. It also work with clinical and basic science Department Chairs to recruit new investigators with expertise in important complementary areas of research, such as Mycobacterium tuberculosis and Herpes viruses.
The Program for Infectious Diseases will build on the outstanding research groups in the Departments of Molecular Genetics & Microbiology, Medicine, and Pathology. These groups have an excellent track record of funding from NIH, WHO, private industry, and other sources. The Program plans to submit a proposal for an NIH training grant for education of pre- and postdoctoral M.D. and Ph.D. students in 1995. Development of an Program of Infectious Diseases will require commitments from the SOM: both clinical and basic science departments will need to commit significant physical, financial and personnel resources to filling the gaps in current research. The Departments of Molecular Genetics & Microbiology, Medicine, and Pediatrics have all made commitments to recruit faculty in this area, but they will need new and/or upgraded facilities to attract and retain first rate scientists.
III. Goals and Resources for Infectious Disease Programs
The Programs in Emerging Pathogens and AIDS research propose to build on existing research strengths primarily by improving research support infrastructure and expanding the breadth of expertise applied to these problems. The Program for Infectious Diseases is proposed as an inter-institutional initiative to coordinate and promote research and educational activities in infectious agents and communicable diseases, and would support the above-mentioned specific programs. The specific goals and resources for the proposed programs include:
Emerging Pathogens. Goals: Submit proposal for Program-based funding by 1/96; recruit Associate Director by 1/96; recruit one or more additional faculty investigators by 12/96. Resources: Start-up support for 2-3 additional faculty; commitment of SOM salary support for one additional investigator; continued commitment of physical resources, including development of P3/P4 animal facilities, in Center for Molecular Medicine.
HIV/AIDS. Goals: develop program as part of NIH GCRC proposal to be submitted in 7/95); develop plan to support recruitment of retrovirologist (by 1/96). Resources: commitment of dedicated space for clinical program and support for conversion/upgrading of facilities.
Program for Infectious Diseases. Goals: secure broad institutional commitment to program development (by 7/95); submit NIH training grant by 1/96. Resources: institutional funds to support training grant proposal; start-up support for new faculty appointments.
ANALYSIS OF INFECTIOUS DISEASE PROGRAMS
STRENGTHS
Excellent clinical and translational program in emerging pathogens Good extramural funding record SUNYSB & regional strengths in basic research Clinical program (Lyme) with excellent profile regionally and internationally
WEAKNESSES
Significant physical infrastructure required for Emerging Pathogens Shortage of institutional resources for AIDS program Need to build epidemiology, cellular immunology and lymphokine biology Need to improve breadth & depth of clinical programs Program for Infectious Diseases lacks focus
OPPORTUNITIES
Build center of excellence with unique resources High potential for commercial collaborations and spin-offs Expand industrial support for AIDS programs Enhance SUNYSB reputation in region
THREATS
Prompt action required to take advantage of current position Requires extensive collaboration to mount full fledged effort Research funding is highly competitive