The US Army Medical Research Institute of Chemical Defense the MRICD at Aberdeen Proving Ground, Maryland
Dr. Margaret Filbert
with Cindy Kronman and Stephanie Froberg

Background
          Located at Aberdeen Proving Ground, Maryland on a peninsula lying between the Bush and Gunpowder Rivers, the Medical Research and Materiel Command's (MRMC) US Army Medical Research Institute of Chemical Defense (MRICD) is the lead laboratory for medical chemical defense research. The goal of the research at the MRICD is to provide warfighters with medical protection against exposure to chemical warfare agents. This mission was established during World War I, the first modern military conflict in which chemical weapons--in this case mustard and chlorine gas--were used. Elements of the Army Medical Department were responsible for defense against chemical weapons during WWI. These efforts were later directed by the Gas Defense Service. Research on the effects of chemical warfare agents and development of treatments for exposure to chemical agents began at Edgewood Arsenal (now Aberdeen Proving Ground) in 1922, with the organization of the Medical Research Division.
           In the early 1960s the Medical Research Division became known as the Biomedical Laboratory, and in 1981, the organization received its present name, MRICD. The institute develops prophylactics, pretreatments, and antidotes, and provides instruction to protect and treat the warfighter on a chemical battlefield. While emphasis is on preventing chemical injuries, research is also directed at accelerating the warfighter's recovery and maintaining combat effectiveness. Col. James A. Romano Jr. is the Commander of MRICD. He holds a doctorate in experimental psychology.
          Scientists at the MRICD conduct research to characterize the effects of various 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 any 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 any 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, such as sulfur mustard, MRICD scientists evaluate topical skin protectants that block penetration of the agent as well as active topical skin protectants that also decontaminate the agent. Once possible pretreatment and treatment compounds are identified, research at the institute evaluates their effectiveness and safety when they are given alone and in combination with established medical therapies.

Research Accomplishments
           Institute scientists have determined the mechanisms and neurochemical events by which nerve agents induce a clinically unique seizure state, evaluated the utility of clinically approved anticonvulsants in dealing with nerve agent seizures, and determined that the standard clinical anticonvulsants are ineffective against the unique seizure state induced by nerve agents. This effort has identified potent centrally acting anticholinergic drugs as potential anticonvulsants and has significantly enhanced our capability to protect against nerve agent-induced seizures through identification of new therapies.
          Scientists developed a topical skin protectant (TSP) against chemical warfare agents to be used in conjunction with protective gear. Named "Skin Exposure Reduction Paste Against Chemical Warfare Agents" or SERPACWA, it is expected to be in production in the near future. As an improvement on this technology, a prototype active topical skin protectant was demonstrated to provide improved protection from both the blister agent mustard and the nerve agent soman.
          The institute is developing chemical agent prophylaxes or chemical agent scavengers based on naturally occurring or artificially mutated enzymes. This effort has resulted in the design, expression, production and evaluation of mutant human butyrylcholinesterase enzymes, (cont. p. 4 - MRICD) (MRICD from p. 3) including a double mutant variant, and has developed novel approaches to producing these enzymes in research quantities. In addition, the institute's chemical agent prophylaxis program has contributed to the development of a reusable decontaminating sponge.
          MRICD scientists also developed research strategies to address previously identified major mechanisms of action of sulfur mustard. They demonstrated that both anti-inflammatory drugs and protease inhibitors can protect against sulfur mustard-induced edema, erythema, and microvesication in animal models. Other research on vesicants demonstrated considerable protection of the cornea following pharmacological intervention and accelerated wound healing following debridement with a carbon dioxide laser. Such accomplishments have earned awards and recognition for the MRICD and several of its scientists. In 2000, the MRICD was the Army Research and Development Organization of the Year in the small laboratory category. Previously in the competition, the institute had twice received Awards of Excellence and a Special Award. MRICD scientists have received several Army Research and Development Achievement Awards. Among them are Capt. Stephen T. Hobson who, with collaborators from other Army laboratories, improved the existing TSP by incorporating into it nanometer scale reactors. The resulting reactive creams provides protection against all of chemical warfare agents, both liquid and vapor exposures, for as long as 22 hours.
          In 1998, Dr Clarence Broomfield received an achievement award as well as a patent for his modifications of the protein butyrylcholinesterase (BuChE) to develop a catalytic bioscavenger that can provide protection against chemical warfare nerve agents. Dr. Broomfield's alterations to human BuChE allow the protein to detoxify nerve agent molecules and prevent their reaction with critical targets in the body.
          Another achievement award recipient that year was MRICD scientist, Dr. David Lenz, who along with scientists from the Walter Reed Army Institute of Research, expanded the concept of how to use bioscavengers to provide protection against nerve agent toxicity. Their research efforts resulted in the reusable sponge for decontaminating skin and wounds. The sponge is composed of a combination of immobilized scavenger enzymes covalently linked to polyurethane foam. After the sponge is used to detoxify nerve agents, it can be regenerated in an oxime solution and reused. This technology holds great promise for protection of medical personnel during patient management and treatment in a chemical environment.
          Several MRICD scientists have authored or co-authored manuscripts that have received best paper honors at Army Science Conferences. In the Biomedical and Behavioral Sciences category, Drs. Tsung-Ming Shih, Steven Duniho and John McDonough won for their paper "Control of Organophosphorus Nerve Agent-induced Seizures is Critical for Neuroprotection and Survival." The paper described the uniqueness of seizures induced by six different chemical warfare nerve agents, the most effective drugs to prevent these seizures, and the necessity of controlling such seizures to prevent acute lethality or long-term brain damage.
          Dr. David Lenz and Donald Maxwell were among the authors of a best paper in the Life Sciences Category, "Exploiting Immobilized Enzymes; Detoxification of Nerve Agents," at the Army Science Conference. Mr. Maxwell was also an earlier recipient of the best paper in the Life Sciences category in for his paper entitled, "Carboxylesterase: Regulatory Control and Peptide-Induced Secretion of an Endogenous Scavenger for Organophosphorus Agents." He shared this honor with collaborators from the Medical College of Georgia and TNO Prins Maurits Laboratory, The Netherlands.
          These research efforts of the MRICD support identified medical countermeasures through their development, fielding, and integration into Army medical doctrine. This is partly accomplished through the institute's postgraduate training of military health care providers in the medical management of chemical casualties. Efforts are also made to optimize patient care through evaluation of available information, the identification of deficiencies in chemical casualty care, and the initiation of applied research to answer these deficiencies.

Research Publications
           Since the 1980s, 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 the CBW threats. Several supplemental issues of the Journal of Applied Toxicology have been published highlighting the research presented at the bioscience meeting: Medical Countermeasures to Botulinum Toxins and Topical Skin Protectants Against Nerve and Vesicating Agents (December 1999), Medical Countermeasures to Vesicating Agents (December 2000) and Medical Countermeasures to Nerve Agents scheduled for December 2001. MRICD's research has also been featured in a special issue of Military Psychology, which focused on the psychological and behavioral effects of exposure to chemical warfare agents. The book Chemical Warfare Agents: Toxicity at Low Levels, edited by Dr. Satu M. Somani and Col. James A. Romano, Jr. (see ASA's review in ASA Newsletter 01-1, 28 February 2001) features many aspects of MRICD's research and is now in its second printing. Particularly timely, the last chapter discusses the emergency response to a chemical warfare incident, describing domestic preparedness, first response, and public health considerations.

Training
           The MRICD's training in the medical management of chemical casualties and its support to U.S. agencies that oversee counterterrorism preparedness are other areas of recognized excellence. Since 1980, more than 19,600 students have been trained in MRICD's Medical Management of Chemical and Biological Casualties Course. Over 9200 of these were trained since 1996, including 2600 in 1999. The American Medical Association has approved Continuing Medical Education credits for physicians and Continuing Education Units for allied health care professionals attending this course.
           In 1999, MRICD developed two additional courses: the Field Management of Chemical Casualties, to train non-medical personnel and first responders, and Train the Trainer, to enable health care providers to train their colleagues. These capabilities are critical elements of national counterterrorism efforts. In 1999, MRICD's training efforts advanced to a completely new scale when the institute conducted a live, multi-day satellite broadcast entitled "Medical Response to Chemical Warfare & Terrorism." Over 780 domestic sites and 13 sites in foreign countries registered to carry the broadcast to an estimated potential viewership of over two million people, making the presentation perhaps the most-watched training course ever conducted. The presentation also received numerous media and broadcast awards, including the Crystal Award of Excellence, in the satellite uplink programming category, presented by the Communicator's Award program. The broadcast was updated with new material and repeated in the fall of 2000.
           The institute's Chemical Casualty Care Division (CCCD) also developed a website at: http://ccc.apgea.army.mil--featuring a variety of their instructional products in the medical management of chemical casualties. Materials from the training courses offered by the division are available for download, including PowerPoint slides from course lectures. Also available on the site is the complete text of Textbook of Military Medicine, Part 1, Medical Aspects of Chemical and Biological Warfare. The site lists descriptions of, and dates for, the Medical Management of Chemical and Biological Casualties Course (MCBC) and the Field Management of Chemical and Biological Casualties. Hyperlinks to related sites are another feature of the CCCD web pages. A third live nationwide satellite broadcast on Biological and Chemical Warfare and Terrorism: Medical Issues was held in late November 2001. Most of the training materials are available at http://ccc.apgea.army.mil.

Conclusion
           Research conducted at the MRICD benefits not only warfighters but has applications in many areas of bio-medical research. 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, epilepsy, and industrial chemical exposures. Past accomplishments of medical chemical defense researchers at APG that have had applicability in the general medical community include significant contributions to the development of modern techniques of cardio-pulmonary resuscitation (CPR) and the definition and description of the role of lung surfactant.
           Through the Army Domestic Technology Transfer Program, the MRICD participates in cooperative arrangements with small and large businesses and universities by sharing government technology and resources. Many U.S. companies, for example, contribute sample compounds, both experimental and commercial, to the MRICD for evaluation as candidate medical therapies for chemical agent exposure. In exchange, the MRICD provides these companies with the results of the evaluations of their compounds. These results could contain unique information that would prove valuable to the companies in the development of their products for the treatment of other illnesses. The government benefits from the innovations of American businesses, while American businesses benefit from the substantial resources of the Federal government.
           "The USAMRICD has had a rich tradition of service to the nation and its armed forces," says Col. James Romano. "Through continued efforts, characterized at times by great progress, and as a result of proliferation of the chemical threat, the laboratory has become an integral part of the US Armed Forces' preparedness. Clearly, the laboratory is realizing its full potential and is being recognized as a world center of excellence in the area of developing medical countermeasures to CW agents, an area so vital to the national defense." Adds Col. Romano, "The future holds great promise for MRICD's dedicated staff. Their outstanding level of technical expertise and the work they are doing and are planning to do will further the knowledge base of all in this most critical area of specialized medicine."

Visit MRICD at http://chemdef.apgea.army.mil/