The U.S. Army Medical Research Institute of Chemical Defense Expands Its Research and Training Mission

David H. Moore. D.V.M., Ph.D. Margaret Filbert, Ph.D.

Introduction

           The U.S. Army Medical Research Institute of Chemical Defense (MRICD) is the U.S. Department of Defense's primary laboratory for conducting medical chemical defense research. The institute, located at Aberdeen Proving Ground, Maryland, is a subordinate command of the U.S. Army Medical Research and Materiel Command, headquartered at Ft. Detrick, Maryland. Since the early 1960s, the research mission of the institute has been directed toward the development of medical countermeasures to protect military personnel from the effects of chemical warfare agents. The research efforts are also directed at minimizing casualties and maintaining combat effectiveness of U.S. military personnel. Colonel Brian Lukey is the commander of MRICD. He holds a doctorate in pharmacology from the University of Louisville and is a diplomate of the American Board of Toxicology. Colonel Harry Slife is the deputy commander. He holds a doctorate in biochemistry from the Uniformed Services University of Health Sciences, in Bethesda, Maryland. The institute meets its mission demands with a scientific and technical staff of over 300 civilian and military employees.

Ongoing Research Mission

           Scientists at the MRICD conduct research involving the full spectrum of classical chemical warfare agents, such as the blister agent sulfur mustard and the nerve agents soman, sarin, and VX, as well as selected biological neurotoxins. They seek to define the biological systems affected by the agent or toxin, and to identify short- and mid-term consequences of exposure. By gathering and analyzing such information, MRICD scientists are able to explore methods of medical intervention. They evaluate compounds that can be given before exposure to prevent or lessen incapacitating effects of the agents and test compounds for their ability to reverse toxic effects after exposure has occurred. For agents that can be absorbed through the skin, MRICD scientists also evaluate topical skin protectants that block penetration of the agent. Once possible pretreatment and treatment compounds are identified for advanced development, institute scientists evaluate the effectiveness and safety of the new countermeasures when given alone and in combination with other therapies.

Research Accomplishments

           Institute scientists were instrumental in the development and U.S. Food and Drug Administration (FDA) licensure of pyridostigmine bromide (PB) as a nerve agent pretreatment. MRICD scientists conducted much of the early research on nerve agent-induced seizure activity and the resulting brain injury. They examined the utility of diazepam as an anticonvulsant and worked with military medical planners and the FDA to rapidly field the first generation antidote for nerve agent-induced seizures. Subsequently MRICD scientists determined that a water soluble benzodiazepine (midazolam) offers significantly improved efficacy. Midazolam is now in advanced development as a second generation nerve agent anticonvulsant. For their efforts in this program, Drs John McDonough, Tsung-Ming Shih and Benedict Capacio have been selected to receive the prestigious 2006 Research and Development Achievement award at the 25th Army Science Conference in Orlando, Fla., November 27-30, 2006.

           MRICD scientists have also developed a topical skin protectant against chemical warfare agents to be used in conjunction with protective gear. This topical formulation is now approved by the FDA as a medical product offering protection from exposure to mustard, nerve agents and biological agents. In collaboration with government and academic research partners, MRICD scientists developed chemical agent bioscavengers based on naturally occurring (plasma-derived), recombinant protein and artificially mutated enzymes. This latter effort has resulted in the design, production and evaluation of mutant human butyrylcholinesterase (huBuChE) enzymes, including a double mutant variant. Mutagenic alterations to huBuChE allow the protein to detoxify nerve agent molecules and prevent their reaction with critical targets in the body. The bioscavenger program holds enormous promise for developing a broad spectrum pretreatment or antidote that will have no observable side effects or produce performance decrements in persons treated with the scavenger. The program has now moved into advanced development and is on a track that could lead to FDA licensure.

Expanded Research Mission and Capabilities

            Recently a program in medical diagnostics was established for verification of human exposure to chemical agents. This program utilizes and refines standard procedures but also supports research efforts to develop novel analytical techniques for verification of exposure. A standard operating procedure for handling and tracking clinical samples was developed and, along with a published technical bulletin, is posted on the MRICD web site at http://usamricd.apgea.army.mil/.

            The U.S. National Institutes of Health (NIH) recently developed a strategic plan and research agenda to address the nation's ability to mitigate injuries resulting from chemical attacks on civilian populations. The NIH and NIH-sponsored research organizations do not routinely have access to facilities approved to use restricted hazardous chemicals such as the chemical warfare agents. In recognition of USAMRICD's expertise in this area, the NIH has sponsored renovation of facilities at the MRICD for the development of a Collaborative Research Facility (CRF). The CRF will allow investigators from academia, other government laboratories, and industry to conduct medical chemical defense research requiring the use of dilute chemical surety materials, obviating the need to build and maintain their own specialized facility for the storage and use of chemical threat agents. This facility will be part of the MRICD Cooperative Research Program (CRP) devoted to excellence in research cooperation across and between governmental and non-governmental entities throughout the U.S. According to Major Maurice Sipos, the CRP director, renovations are expected to be completed in early 2007. This CRF will provide over 6000 square feet of dedicated laboratories, offices and laboratory animal facilities.

            Most recently, the NIH and USAMRMC have signed four interagency agreements that provide support from NIH for research at MRICD addressing critical needs for medical protection of civilian populations. This interagency cooperation will benefit both the DOD and the NIH and is expected to extend into future years.

Training

            The MRICD, in partnership with the U.S. Army Medical Research Institute of Infectious Diseases, conducts the Medical Management of Chemical and Biological Casualties Course. This course is designed for physicians, nurses and other medical professionals and is accredited for Continuing Medical Education (CME) units through the American Medical Association. The U.S. Government Accountability Office has identified this course as the military "Gold Standard" for the nation. Since 1980, more than 20,000 students have been trained in this course both at the laboratory and at remote locations around the world. An additional course offering, the Field Management of Chemical and Biological Casualties Course, provides the only course extant in the United States that focuses on advanced training for pre-hospital medical providers and emergency responders to efficiently and effectively manage incidents involving chemical warfare agents and biological threat agents. Since its inception, in 1985, over 3,900 students have been taught in this course. Accreditation for EMT/NREMT students is obtained through the Continuing Education Coordinating Board for Emergency Medical Services. Both of these courses are approved by the Department of Homeland Security as eligible for grant assistance.

            MRICD has also co-hosted a total of nine live satellite broadcasts since 1997. The most recent satellite program, "Biological & Chemical Warfare and Terrorism: Advanced Topics on Medical Defense Against Biological and Chemical Agents," aired in 2002-2003 and educated over 46,000 students. Following live programs, these satellite courses are continuously offered in DVD/VHS format.

            The most recent course added to the MRICD curriculum is the Hospital Management of Chemical, Biological, Radiological/Nuclear and Explosive Incidents (HM-CBRNE) Course. This course is designed to equip military and civilian hospital-based medical and management professionals with skills, knowledge and information resources to carry out the full spectrum of health care facility responsibilities required by a chemical, biological, radiological/nuclear, explosive, (CBRNE) or mass casualty event. This course offers continuing education credits for physicians, nurses, and EMT/paramedics. Since December 2004, more than 300 students have obtained training in this course.

            The institute also developed a website, http://ccc.apgea.army.mil, featuring a variety of instructional products in the medical management of chemical casualties. Materials from the training courses offered are available for download, including PowerPoint slides from course lectures. Also available on the site is the complete Textbook of Military Medicine, Part 1, Medical Aspects of Chemical and Biological Warfare.

Institute Outreach and Scientific Exchange

            For the past two decades, MRICD has sponsored a biennial scientific conference, the Medical Defense Bioscience Review. The Bioscience Reviews have traditionally been an excellent forum to discuss the science of medical chemical defense. As an avenue for advancing and communicating knowledge among the participants, the conference challenges attendees to explore and develop better countermeasures for the best possible medical protection against chemical threats. The 15th Bioscience Review was held at the Marriott's Hunt Valley Inn and Conference Center in Hunt Valley, Md., on 4-9 June 2006. The conference theme was "Science and Technology Capabilities for Medical Chemical Defense."

            In 2002 MRICD established an online Journal of Medical Chemical Defense www.JMedCBR.org and the inaugural issue was posted in October 2003. The focus of the journal has been expanded to now include medical biological and radiological defense and sponsorship of the journal was assumed by the Defense Reduction Threat Agency. Dr. David Moore continues as editor for medical chemical defense and Dr. Margaret Filbert serves on the editorial advisory board.

            Industry partnerships are vital to the rapid development and deployment of medical products. MRICD has numerous cooperative research and development agreements with commercial and industrial organizations as well as contracts and agreements with academic institutions wherein the collaborating partner produces the medical countermeasures developed by MRICD. MRICD scientists evaluate the efficacy of the products against chemical warfare agents. International cooperation is also vital to maintaining a vibrant research program. The institute routinely participates in formal data exchanges with NATO partners as well as in numerous bilateral exchanges with allied nations. Institute scientists participate in national and international scientific conferences and publish their research results in peer-reviewed scientific journals.

Conclusion

            Research conducted at the MRICD not only benefits military personnel, but now also addresses serious concerns of civilian emergency preparedness planners. The knowledge afforded the nation by the subject matter experts at MRICD and application of the findings and products of the institute are central to a national strategy to mitigate the health effects of terrorist use of toxic chemicals. Results of research with treatments and pretreatments for chemical agent exposure can prove valuable in the treatment of other medical problems, such as Alzheimer's disease and epilepsy.

Ed. Note: ASA thanks Drs Moore and Filbert for their well written, interesting and informative article which provides an update on the noted and appreciated USAMRICD. To the professionals around the world, USAMRICD represents the very heart of the US Armed Forces medical science.