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RESEARCH PRIORITIES AND FUTURE RESEARCH PROGRAMS

L.S. Sandakhchiev*, R.A. Martyniuk, S.V. Netesov

State Research Center of Virology and Biotechnology VECTOR

I realize that this is rather a broad, indeterminate and subjective task to define research priorities and future research programs.

First of all, I believe we should consider the future forecasts developed by professional experts. The Russian Academy of Sciences gives its great attention to this issue, and the Academy's two most recent general meetings were dedicated to discussing the most rapidly growing areas of science: nanotechnology, genomic, information technology etc.

A systems approach at analyzing the future development of technology has been taken by RAND National Defense Research Institute in the year 2001 in [The Global Technology Revolution. Bio/Nano/Material Trends and Their Synergies with Information Technology by 2015. Prepared for the National Intelligence Council. RAND National Defense Research Institute. Philip S. Antуn, Richard Silberglitt, James Schneider; [http://www.rand.org/publications/MR/MR1307/MR1307.pdf]. Another similar document was prepared for the US National Intelligence Council [Global Trends 2015: a Dialogue about the Future with Nongoverment Experts; http://www.cia.gov/cia/reports/globaltrends2015/globaltrends2015.pdf]. It is anticipated that advances in bio-and nanotechnology, new materials and information technology, in their synergy, would create systems and devices that would produce a global effect on health and personal safety; economic and political systems; business and trade. The emerging technological revolution, together with globalization efforts, would become a reality, thanks to information technology and continued transportation improvements. Besides positive effects, such as longer life spans, economic prosperity and higher life quality, there would emerge ethic and privacy problems (e.g., biomedical research, cloning, stem cells).

Quite impressive advances are anticipated in genomics thanks to improvements in DNA sequencing techniques, genetic manipulations on living organisms, computer-assisted modeling; mechanisms of the living thing would be discovered and this would create a basis for design and assembly of new living organisms, with microbes and virus as a first step.

DNA sequencing and analysis would open up possibilities for the molecular diagnosis of diseases; cost-effective drug discovery, disease prediction and allow the prediction of the spread of diseases both within ethnic groups and global populations; they would revolutionize criminalistics, create possibilities for the development of biosensors for pathogen detection in the environment, i.e. in water, air, food, which would allow an online monitoring over the biosphere. Genotyping infectious agents and discovery of characteristic features of the host's key genes would allow one to predict the course of disease.

Cloning, especially the human cloning, is an area that holds promise for inevitable and rapid development in spite of numerous ethic and religious issues surrounding it.

Genetically modified organisms. We have already got used to genetically engineered, microorganism- or cell line-based producers of drugs, e.g. insulin, interferon, erythropoietin etc. We now begin to realize the vast potential of transgenic plants for humankind. Soon, we would consume edible vaccines and witness therapy of genetic human defects, most likely by using in vitro approaches.

Therapies and drug development. Novel approaches to therapy would allow one to control the immune system and overcome drug addiction. The drug discovery and development itself would heavily rely on computer simulations and high-resolution physical methods, e.g. atomic-force microscopes, mass spectroscopy, and scanning probe microscopes. We should also expect to see a synergy effect of combinatory approaches and those based on computer simulation of drugs. Profound changes in preclinical and clinical assessment of drugs are likely to occur, which would allow one to accelerate and/ or make less expensive the development of new drugs.

Biomedical engineering. Significant advances in tissue engineering are likely to occur. In particular, it is believed that treatment of heart diseases via growth of functional tissue by 2015 is a realistic goal. In spite of ethic and legislative restrictions of use of the stem cells, great advances are expected to take place in this area through private financing. Advances would also be achieved in xenotransplantation of organs, including those obtained from genetically modified animals. Certainly, we could expect progress in conventional approaches involving the use of artificial organs based on biocompatible materials in such areas as eye, hearing, and nervous system repair.

Experts place their high expectations on advances in nanotechnology and nanomaterials. These technologies would have broad applications. Diagnostic microchips would allow rapid simultaneous analysis of thousands of parameters, which is essential to the on-line detection of pathogens in the environment and the human or animal body. Nanoemulsions of drugs would allow us to make use of transdermal and oral drug delivery to the human body. A more detailed assessment of this direction can be found in Nanotechnology Research Directions: IWGN Workshop Report Vision for Nanotechnology Research and Development in the Next Decade. Edited by M.C.Roco, S.Williams, P.Alivisatos [http://www.wtec.org/loyola/nano/IWGN.Research.Directions].

Everyone agrees that information technology would even more rapidly develop in the future and its integration with other technologies would move the technological revolution to the most remote places on our planet.

An impressive analysis of our future was performed by Dr. Stephen M. Younger, a leading physicists who currently heads the Defense Threat Reduction Agency (DTRA) in [Supercomputing and the Human Endeavor: The Coming Scientific Revolution in How We Use Machines to help us Think http://www.lanl.gov/sche/pdfs/schewhiteppr012201.pdf]. In the author's opinion, the future would be determined by three major revolutions: two scientific - in biological science and supercomputing - and one social that would be the result of the first two. According to him, by the end of this decade the rate of supercomputers would reach and exceed one thousand operations per second, which would open up new possibilities in computer simulation. It would allow one to model living objects at an atomic level and to look into answering questions like: "What is life? What is the difference between the dead and the living matter? What determines an ensemble of organic molecules to acquire properties of the living matter?" The revolution in supercomputing would actually create an economy based on knowledge, and computers would help us produce this knowledge, which would allow us to predict and control the social development.

The technological revolution would produce benefits for humankind but it would also increase potential threats. Thus, terrorist groups are likely to actively use the advances in technology in their illicit activities. As the globalization process moves forward, enhancing international collaboration becomes vitally important. I should note that successes are likely to occur in various areas of international collaboration but I would like to note three such areas:

First, I would like to address problems related to infectious diseases. In nature, there is a great variety of viruses, bacteria, and fungi causing diseases in humans, animals or plants. Experts estimate that currently we are aware of far less than 1 percent of existing viruses and several percent of microbes. Nature is continuously creating new pathogens, the so-called "emerging infections", and this potential is just inexhaustible. The most recent example of this is the SARS situation, a disease known as Severe Acute Respiratory Syndrome. During the last 20 years alone, over 30 new infectious agents e.g. HIV, Marburg, Ebola, Machupo, Nipah virus and SARS-associated coronavirus have been discovered against which no efficient treatments are available so far.

An outbreak of disease elsewhere on the globe can now be viewed as a threat to any other region of the world. Once an infectious disease, or the insects and animals that carry it, invades a new country or continent, it can prove difficult - if not impossible - to control. This has been the case with West Nile fever, which made its initial appearance on the American continent in 1999 and is now firmly entrenched and spreading [Heymann D.L. Strengthening Global Preparedness for Defense against Infections Disease Threats. WHO, 2001. http://www.who.int/emc/surveill/index.html]. Even high economic development of these countries did not hinder the spread of this infection. According to the Centers for Disease Control and Prevention (CDC), by September 2002 West Nile virus activity had been documented in 42 states and the District of Columbia: 1 460 human cases of the West Nile virus were reported, with 66 deaths. [West Nile virus in the United States - Update 3, 2002. http://www.who.int/disease-outbreak- news/n2002/september/17september2002.html]. Initial costs associated with cases of West Nile fever in New York were placed at almost $100 million. [Heymann D.L. Strengthening Global Preparedness for Defense against Infections Disease Threats. WHO, 2001. http://www.who.int/emc/surveill/index.html]. Health Canada reported 17 suspected cases of West Nile, 3 confirmed cases, including 1 death. [West Nile virus in Canada - Update 2, 2002. http://www.who.int/disease-outbreak-news/n2002/september/20september2002.html].

Known diseases such as influenza, TB, malaria and some others, through their changeability, can relatively easily overcome conventional immunization and drug-based approaches to prevention and therapy.

The human kind has been fighting a biological war against microbes since its emergence and even now, according to WHO, infectious diseases account for 24.7 percent of fatality worldwide. In developing countries with public health underfunded, this figure increases to 45 percent. Infantile mortality from infectious diseases reaches 63 percent of all infantile deaths, and 48 percent of untimely deaths (under the age of 45) are brought up by infections [Communicable diseases 2000. WHO/CDS/2001. http://www.who.int/infectious-disease-news/CDS2000/index.html, Anker M., Schaaf D. WHO Report on Global Surveillance of Epidemic-prone Infectious diseases //WHO/CDS/CSR/ISR/2000.1; Heymann D.L. Strengthening Global Preparedness for Defense against Infections Disease Threats. WHO, 2001].

Though biological weapons-and bioterrorism experts often operate with a limited list of several dozens of infectious agents on it, we should not underestimate the possible terrorist use of any of diverse pathogens existing in nature.

So the task of establishing a global system of surveillance of possible natural or artificial outbreaks is far more difficult than that of chemical agents or explosives.

It is important to realize that biological agents act in time, have a latent period during which the carrier of infection may find herself/himself in another city or even country, where the outbreak of disease may be actually identified, and it may take much time to prove the bioterrorist use of microorganisms since it will require a comprehensive epidemiological analysis, e.g. investigation of all the stages of manufacture and distribution of food-stuffs in case of food poisoning.

A qualitatively more difficult problem is that of keeping the inventory of the pathogens during research work since during such activities the biological agents, as a rule, grow in quantity and can be represented by not only individual pathogens but also by being present in experiment in the form of infected cell cultures, laboratory animals etc. Insignificant, hardly accountable quantities of a biological agent, may pose a real threat in terms of uncontrolled leakage of biological material. Unfortunately, this problem does not yet have either an engineering or technical solution. In fact, it is determined by the human factor, i.e. it is necessary to adopt criteria and requirements to personnel to be allowed to work with pathogens, even within the highly secured laboratory facilities.

An associated problem is that highly pathogenic agents are many and they might be accessed during natural outbreaks of disease. Moreover, they can be engineered through simple laboratory manipulations on the non-pathogenic microorganisms available. The well-known case of the terrorist use of Salmonella in a salad bar in Oregon in 1984 resulted in sickening over 700 individuals. However, first it was regarded to be a natural outbreak and only one year later it was proven that Salmonella was used by religious cult extremists to prevent voting in Oregon. By the way, the US public learned about that many years after.

Therefore, it is medical staff that turn out to be the first to have to deal with biological incidents and it is the public health capabilities that determine the preparedness of a country, region or city for a timely detection and elimination of consequences of the use of biological agents. Therefore, financial and organizational efforts should be focused on civilian rather than military agencies.

The nation must be prepared to deal with detection and elimination of consequences of outbreaks cased by any biological agents, including both conventional and exotic species of microorganisms. The existing national systems of nation-wide epidemiological surveillance and control of infectious diseases should be capable of identifying, containing and eliminating an infectious disease outbreak regardless of whether it is the result of natural manifestation of a pathogen or deliberate use of a natural or genetically modified organism [6, 7, 11, 12, 13].

I wanted to point out these features of control over biological agents and to say that that international collaboration in this area is both extremely important and urgent in order to set up a system of efficient alert and response. This issue was specifically addressed in May 2001 during the 54th World Health Assembly in the report by the Secretariat "Global Health Security - Epidemic Alert and Response" [http://www.who.int/gb/EB_WHA/PDF/WHA54/ea54r14.pdf]. It was noted that in 1995 the World Health Assembly adopted resolutions WHA48.13 on new, emerging and re-emerging infectious diseases and WHA48.7 on the revision and updating of the International Health Regulations. The WHO totally realized the need for enhancing epidemiological and laboratory surveillance at national level as "the main defense against the international spread of communicable diseases".

The WHO Secretariat pointed out the increased possibility of intentional use of agents causing infectious diseases and emphasized that natural epidemics and those due to the deliberate use of biological agents may manifest themselves in the same manner.

In 1997, WHO established a special system to seek, collect and verify information on reported outbreaks based on close cooperation of WHO Collaborating Centers with governmental and nongovernmental agencies, which is available as confirmed disease outbreak news on the WHO web site (www.who.int/disease-outbreak-news/) and in the WHO Weekly Epidemiological Record (www.who.int/wer). At global level, laboratory networking takes place (http://www.who.int/csr/en/), focusing on such infections as hemorrhagic fevers (including Ebola virus), poliovirus; preparation of databases such as the WHO antimicrobial resistance data bank (ARInfoBank) (www.who.int/emc/amr.html), influenza FluNet (http://oms2.b3e.jussieu.fr/flunet/), rabies RabNet (www.who.int/emc/diseases/zoo/rabies.html), and some others. WHO also called the member states to establish partnerships to involve both civilian public health and military medical capabilities.

WHO continuously draws the attention of its member states to the ultimate role of national potential to ensure epidemiological welfare of other countries and so it plans to expand national training programs in intervention epidemiology worldwide, and the Training in Epidemiology and Public Health Interventions Network (TEPHINET). Major conclusions based on discussions of the Secretariat Report were reflected in resolution WHA54.14 "Global Health Security: Epidemic Alert and Response" (http://www.who.int/gb/EB_WHA/PDF/WHA54/ea54r14.pdf). A good example that deserves serious attention and similar action is the establishment of the WHO Bureau in Lyon (France) as a model for using national potential to contribute to training of personnel for countries at high epidemic risk (http://www.who.int/infectious-disease-news/newsletter/vol2-6September-October2001/vol2-6-eng.pdf).

At a global level, huge resources to combat infectious diseases are available already. Certainly, these will be used to counter bioterrorism incidents [6]. They include hundreds of WHO Collaborating Centers worldwide specializing in certain infections; a Pan-American Health Organization (PAHO) laboratory network; International Clinical Epidemiology Network (INCLEN); the Pasteur Institutes network; international research centers network of the National Institutes of Health (NIH) that involves many universities across the USA; Centers for Disease Control (CDC) in numerous countries many of which conduct epidemiological surveillance and provide field epidemiology training for different regions. US Army and Navy also established a specialized network of research centers in several countries. It should be noted that this particular resource is very much focused on specific tasks and, except for the Epidemiologic Intelligence Service (EIS) centers, is not oriented on detection and identification of the entire pathogen range.

As a matter of fact, to localize and contain unusual outbreaks posing threat to global public health WHO has set up taskforces to be deployed during the life of such outbreaks.

In these pictures, the WHO shows examples of epidemics that have occurred during the recent years with economic losses they produced. They have been eliminated under the WHO aegis, using this principle (http://www.who.int/emc/pdfs/global_epi_detection_response.pdf). Such a scheme, as simple as it may seem, requires tremendous efforts in terms of coordination, material supply, transportation, communication activities, etc.

Another approach was proposed by an outstanding epidemiologist Dr. D.A. Henderson [7] who, based on many years of his experience as the leader and actual participant in the global smallpox eradication program, arrived at the conclusion that fixed-site international centers be established in 15 regions of the world. These should include:

Systematic studies of a specific region make it possible to obtain invaluable databases, investigate into different factors that can influence the epidemiological situation, and identify unusual cases requiring careful examination.
The World Health Organization together with the International Center of Genetic Engineering and Biotechnology (ICGEB) and several nongovernmental organizations - Program for Appropriate Technology in Health (PATH), International Clinical Epidemiology Network (INCLEN) and Training Program in Epidemiology and Public Health Interventions Network (TEPHINET), the so-called Alliance against Infectious Diseases, in the follow-up of the US Institute of Medicine recommendations prepared (in 2000) a program proposal "Global Monitoring, Research and Training to Control Infectious Diseases" (http://www.fas.org/bwc/papers/allaid.htm).

In the initial stage of the program, 10-12 laboratories or institutes would be identified that would located in strategically important regions at high epidemic risk and with insufficient surveillance capabilities. Those laboratories should have laboratory and clinical study capabilities and a potential for conducting epidemiology work, access to air and ground transport, possibility of telecommunications installation, and prospects for the center's future expansion.

Centers thus identified would have a WHO Collaborating Center's status and preferred access to WHO programs and those of Health Ministries in state-parties, and they would be coordinated by the WHO Office of the Strategic Alliance.

Each center, in its turn, would be established taking into account the region's specific needs and, in the initial stage, provided with necessary resources to create the most advanced potential for diagnostic, clinical and epidemiological activities. It also would be provided with telecommunications to be able to communicate with the other centers as well as regional, federal, and international agencies involved in infectious disease surveillance and response.

Each center would establish regional networks to include clinics, institutes, education establishments and others and it would have intensive participation in the region's infectious disease programs. The regional network would involve enterprises manufacturing specialized pharmaceutical products that, through technology transfer, would be given an opportunity to meet the region's needs for standard diagnostic tests and therapeutic products.

The regional network should also involve research laboratories that develop diagnostic and therapeutic products as well as vaccines; biosafety research laboratories studying the safety of biological substances and microorganisms to humans and the environment.

The program envisages that within 8-10 years a worldwide network of regional centers would be up and running and so a long-term sustainable regional potential for communicable disease control would be created. It is proposed that some of these centers would become the centers of excellence like CDC, NIAID, and ICGEB.

The authors note that the proposed approach would represent the most reliable way of prevention of and dealing with possible future pandemics (for more information, send a message to WHO at allaid@who.int).

The USA that has longstanding experience in infectious disease control all around the world in the year 2000 developed a Biological and Chemical Terrorism: Strategic Plan for Preparedness and Response Recommendations of the CDC Strategic Planning Workgroup [3] that involves coordinated response to and elimination of such events by over 10 agencies. This plan is focused on five major areas:

All these areas propose personnel training, investigation of and total preparedness for detection and elimination of consequences of the possible attack using chemical or biological agents in all the states and cities. The key point is to design a multi-level laboratory network to efficiently warn public health authorities at community, state, district and city levels about biological and chemical agents detected. This plan is aimed at significant reengineering of the existing infrastructure dedicated to infectious disease response and control.

To detect and counteract bioterrorism, the National Institute of Allergy and Infectious Diseases (NIAID/NIH) has developed a biodefense research agenda for CDC A Category Pathogens such as smallpox, plague, tularemia, anthrax, botulinum toxin, etc. (http://www.niaid.nih.gov/biodefense/research/biotresearchagenda.pdf). As part of this strategic plan, the NIAID is establishing the Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCE) Program and Biocontainment Laboratories (BL) (http://www.niaid.nih.gov/biodefense/rblrce.htm). The RCEs and BLs will contribute to the need for new infrastructure and research resources necessary for identifying and responding to emerging diseases and bioterrorism events. In addition, the centers will:

The idea of international/ regional centers of excellence seems to be very promising. Thus, SRC VB VECTOR, with US DHHS Biotechnology Engagement Program's support, is carrying out an ISTC project aimed at developing a concept for the establishment of an International Center for the Study of Emerging and Re-emerging Infectious Diseases (ICERID). By an International Center we mean an international organization established by an intergovernmental agreement, similar to those of ISTC or the Joint Institute for Nuclear Research in Dubna, CERN in Switzerland or International Center for Genetic Engineering and Biotechnology in Trieste (Italy). Though the process of establishing the International Center is complex and may take several years to complete, the proposed arrangement would provide for a long-term strategic collaboration, which is far less subject to political or economic conjuncture fluctuations in Member States. International partnership would accelerate and facilitate the study of dangerous pathogens and the development of state-of the-art products for diagnosis, prophylaxis and therapy for public health and countering bioterrorism. It is, however, important to establish an appropriate regimen of use of infectious agents and scientific results obtained to avoid their possible misuse for illicit purposes. In developing a research program for the proposed international center, it makes sense to include research directions developed by the US leading experts that underlie the NIAID Biodefense Research Agenda (see in below). In developing the ICERID concept, we specifically looked into those research directions that are marked by turquoise-blue:

Immediate Research

Intermediate and Long-Term Research

Over the recent years, programs have been developed in Russia, under the aegis of the Russian Ministry of Health. These are aimed at the development of protections against infectious diseases such as smallpox or SARS, etc. In their major directions, these programs coordinate well with the Biodefense Research Agenda developed by the NIAID experts. It is important, therefore, that collaboration agendas be developed to address these research challenges, which would definitely accelerate and make less expensive practical research outcomes.

REFERENCES

1. R. Preston. The Bioweaponeers. The New Yorker, March 9, 1998, p.52-65.
2. R. Preston. Bio-Warfare-Fiction and Reality, Genetic Engineering News, March 1, 1998, p. 6-39.
3. April 21, 2000 / 49(RR04); 1-14 Biological and Chemical Terrorism: Strategic Plan for Preparedness and Response Recommendations of the CDC Strategic Planning Workgroup.
4. Chemical and Biological Terrorism. Research and Development to Improve Civilian Medical Response. Committee on R&D Needs for Improving Civilian Medical Response to Chemical and Biological Terrorism Incidents. Health Science Policy Program. Institute of Medicine and Board on Environmental Studies and Toxicology. Commission on Life Sciences. NATIONAL RESEARCH COUNCIL. National Academy Press, Washington, D.C. 1999.
5. Proceedings of the Eleventh Amaldi Conference on Problems of Global Security (November 18-20, 1998, Moscow, Russia). Moscow "Nauka" 1999.
6. Emerging infections. Microbiological threats to health in the United States, J. Lederberg, R.E. Shope and S.C. Daks, Jr., Ed. National Academy Press, Washington, D.C., 1992
7. Emerging viruses, S.S. Morse, Ed., Oxford University Press, 1993
8. Lev S. Sandakhchiev and Sergei V. Netesov. Strengthening the BTWC through R&D Restructuring: The case of the State Research Center of Virology and Biotechnology "Vector". The Role of Biotechnology in Countering BTW Agents. 2001 Kluwer Academic Publishers. Printed in the Netherlands.
9. S. Netesov, L. Sandakhchiev. The Development of a Network of International Centers to Combat Infectious Diseases and Bioterrorism Threats. The ASA Newsletter, February 19, 1999, Issue Number 70, PP. 2-6.
10. Lev S. Sandakhchiev. The Need for International Cooperation to Provide Transparency and to Strengthen the BTWC. E. Geissler et al. (eds.) Conversion of Former BTW Facilities, Kluwer Academic Publishers. Printed in the Netherlands, 1998, PP. 149-156.
11. Onischenko G.G., Sandakhchiev L.S., Netesov S.V., Shchelkunov S.N. Bioterrorism as a National and Global Threat. Zhournal Microbiologii, Epidemiologii i Immunologii (Journal of Microbiology, Epidemiology and Immunology). 2000, N 6 (in Russian).
12. G.G. Onischenko, L.S. Sandakhchiev, S.V. Netesov, R.A. Martyniuk. Bioterrorism, a National and Global Threat. Vestnik Rossiiskoy Academii Nauk (Russian Academy of Sciences Bulletin). 2003, V. 73, N3, P. 195-204 (in Russian).
13. M.A. Paltsev. Biological Weapons Is an Issue of Russia's National Security. Zhournal Natsionalnaya Bezopasnost (National Security Journal). 2002, N 5 (in Russian). Also available at http://www.mvd-expo.ru/ns/jurnal5/biolweapon.htm

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Proceedings of First Russian Workshop on Biological Security
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