About FDA

Science at CVM in 2012

Gorka Garcia-Malene, OCD, and Morgan riding camels and watching the sunset on the dunes in Morocco. Photo by tour guide

CVM places strong emphasis on its scientific capacity. Without supporting research, CVM’s ability to protect human and animal health would be diminished. Our Office of Research (OR) located in Laurel, Md., addresses current and evolving regulatory issues related to the safety of animal-derived food and animal health products. OR scientists work together to conduct basic and applied research using animals and animal systems. This research focuses on veterinary drug compounds as well as veterinary pathogens that pose potential health risks to animal health and human food safety. Highlights of CVM’s scientific achievements from FY2012 are described below.

Veterinary Laboratory Response Network (Vet-LRN)

During the melamine in dog food poisoning crisis in 2007, CVM scientists realized that they needed a way to seamlessly obtain or share information with state and academic veterinary diagnostic laboratories that respond to chemical and microbial feed or drug contamination events. In 2010, CVM obtained funding that led to developing Vet-LRN, a lab networking program enabling CVM to partner with veterinary diagnostic laboratories nationwide to document, investigate, and diagnose animal feed, pet food, and animal drug-related illnesses.

By the end of FY 2012 Vet-LRN included 28 Tier 1 laboratories (Tier 1 includes hospitals, and public or private diagnostic laboratories), nearly double the number (16) of FY 2011. During the last year, Vet-LRN:

  • Communicated with 28 member laboratories via monthly calls, email newsletters and website updates.
  • Conducted 23 in-depth case investigations and multiple case evaluations.
  • Began leading CVM’s testing program to investigate the root cause of jerky pet treat illness cases.
  • Managed 11 Vet-LRN Cooperative Laboratory Agreement Salmonella Projects(V-CLASP). See subsection below for discussion of the projects.
  • Initiated a proficiency testing program in collaboration with the Illinois Institute of Technology and the University of Iowa. We conducted three proficiency tests, one for copper and two for Salmonella which demonstrate ruggedness of the harmonized V-CLASP method and documented individual laboratory performance.
  • Continued collaboration with FERN in testing animal feeds for pathogens, and pig tissues for triazines.
  • Awarded 23 cooperative agreements with Vet-LRN laboratories providing infrastructure funding for Vet-LRN activities including testing during investigations.
  • Helped plan and participated in National Level Exercise 2012 (NLE12), held in June 2012. NLE12 examined the nation's ability to coordinate and implement prevention, preparedness, response, and recovery plans during significant cyber events. This was the first time multiple FDA centers and offices participated in a national level cyber based exercise, and more than 250 FDA personnel served as exercise players or evaluators. By participating in NLE12, FDA strengthened its capabilities for responding to cyber- attacks, ensuring the agency's ability to carry on its critical functions in the face of such a threat.
  • Became a member of the Integrated Consortium of Laboratory Networks (ICLN) in May 2012 and participated in an ICLN exercise. ICLN is a federal system of laboratory networks providing timely, high-quality, and interpretable results for early detection and effective consequence management of acts of terrorism and other events such as natural disasters and disease outbreaks requiring an integrated laboratory response. Vet-LRN helped plan the ICLN Table Top Exercise, which took place in September 2012. The exercise tested the efficient coordination of analytical laboratory services for a chemical adulteration of a food commodity.

Salmonella Evaluation (V-CLASP) Projects

Vet-LRN awarded 11 cooperative agreements with Vet-LRN laboratories to participate in a study entitled, Evaluation of Salmonella in Symptomatic and Asymptomatic Pets. During 2012, V-CLASP labs developed harmonized methods for isolating Salmonella from dog and cat feces. In addition, the group harmonized documents including a pamphlet for animal owners describing the study goals, definitions, sampling protocol, health history questionnaire, format for reporting results, and FAQs for veterinarians and owners of positive animals. Two proficiency tests demonstrated the ruggedness of the harmonized method and documented individual laboratory performance.

This study will help CVM determine the general prevalence of Salmonella in the dog and cat population. By collecting isolates, CVM will understand the impact of animal feed contamination on both animal health and asymptomatic carrier states, as well as how that information relates to human Salmonellosis outbreaks. The harmonized methods will assist in investigations of Salmonella contaminated feed products to assess impact on the pets in the household and potential carrier states, which could affect the pet owners and public health.

The study laboratory work is expected to be completed by end of 2013. Benefits were already evident in the 2012 Salmonella infantis outbreak, most likely caused by a contaminated pet food product. Vet-LRN laboratories assisted CDC and FDA during this outbreak by testing pet samples from households with human patients.

Stem Cell Research

CVM is developing guidance on how to regulate animal stem cell products. Identifying and characterizing stem cell products are an integral part of assessing safety and effectiveness, and a major component of the quality control parameters for these types of products.

Accurate veterinary stem cell characterization research will help reviewers evaluate stem cell products. Accordingly, we initiated a groundbreaking study, Defining markers of stemness in canine mesenchymal stem cell products from various tissue sources. The ability to distinguish stem cells from other cell types is a fundamental component of the drug evaluation process for stem cells. The study is looking at cell surface markers and messenger RNA in canine fat and bone marrow-derived stem cells. These cells, mesenchymal stem cells (MSCs), can mature into fat cells, bone cells, or cartilage cells. The purpose of this work is to identify cell surface markers to distinguish these stem cells from non-stem cells. Defining stem cell markers helps characterize the product for consistency in manufacturing and chemistry, and also helps to evaluate the safety and effectiveness of these products.

Using analytical methods to detect cell surface markers and messenger RNA for the surface markers in mesenchymal stem cells, we have identified five cell surface markers and twelve messenger RNA markers that describe canine adipose and bone marrow-derived MSCs. The results will be further verified by individual real-time Polymerase Chain Reaction (PCR) assay.

This study will serve as the model for future work using stem cells from different species, including evaluating stem cell markers of equine MSCs. Future research may also address topics such as evaluating stem cells for safety and effectiveness (e.g. cell plasticity, survival and migration, and tumorigenicity potential).

Progress in Nanotechnology Research

The application of nanotechnology in veterinary medicine, in particular the expanding area of nanopharmaceuticals, shows great promise. These products, however, raise numerous food safety questions when considering use in food producing animals. Gaining a better understanding of nanotechnology remains an FDA and CVM priority. Having a directed research program focused on investigating biodistribution of various nanomaterials in food animals is critical to developing future guidance for approving nanopharmaceuticals as animal drugs.

OR completed its first nanotechnology study entitled, Effect of nanogold particles on in vitro genomic assays. We also approved a protocol for a study of the in vivo biodistribution of various nanomaterials in edible animal tissues and by-products. Collaborations with scientists from FDA’s Center for Devices and Radiological Health, the U.S. Navy Research Laboratory, and the Howard University nanoscale facility were all instrumental in establishing our nanotechnology research program. The OR laboratory infrastructure was also upgraded during the year so that nanotechnology animal studies can now be conducted in a more timely manner, which will allow CVM to rely less on external institutions for assistance.

Whole Genome Sequencing of Animal and Zoonotic Pathogens

CVM is responsible for developing methods for effective screening, detection, and identification of pathogens in foods derived from animals, and for ensuring the safety and effectiveness of drugs used in veterinary medicine. Many bacterial pathogens important in veterinary medicine and food production are poorly understood by the scientific community because bacterial genetic information is not available. Such information would be useful in developing vaccines and tests to detect and monitor infectious diseases.

OR has undertaken a study intended to provide the complete genetic sequences of important animal pathogens. Determining whole genome sequences (complete DNA sequences) for pathogens of veterinary importance will have an enormous positive effect on the type of in-depth studies that could be designed to address animal health, drug effectiveness, and regulatory decision-making. We obtained whole genome sequences for 13 of the 20 veterinary pathogens included in this project and we will submit all of these results into the databases at the National Center for Biotechnology Information so they will be publicly available.

Sequence Analysis of Multi-Drug Resistant (MDR) Plasmids and Whole Genome of Foodborne Bacteria Pathogens

Multi-drug resistant (MDR) Salmonella enterica strains are a significant public health risk, but we have little data explaining how the bacteria are spread or why they persist. Also, we do not know why certain serotypes or clones of Salmonella are frequently associated with human infections and antibiotic resistance. Many studies have shown that bacterial plasmids (mobile genetic elements) play an important role in bacterial infections and that genes for antibiotic resistance are commonly found on plasmids.

We selected 50 MDR Salmonella strains for the MDR project and are using analyses of the entire genomic and plasmid DNA sequences of these strains to study relationships between specific genes and the ability of the bacteria to cause severe disease and maintain genes that cause MDR. OR is working on methods of plasmid isolation and performing plasmid typing. We have sequenced the genomes of several Salmonella Heidelberg isolates from food borne disease outbreaks associated with ground turkey and chicken livers. This study will increase our understanding of how genes work together to increase the severity of Salmonella infections. Determining how antibiotic resistance genes work will help identify ways to limit the spread of antibiotic resistance.

In addition to the MDR Salmonella project, we are also participating in an FDA-wide whole genome sequencing project and have submitted 230 Salmonella isolates for this large collaborative study. At the end of the year, we were selecting and preparing an additional 200 strains of Salmonella for inclusion in this study.

Developing Regulatory Assays Using DNA Barcoding

The goals of this study are to develop molecular identification methods for targeted species, and to validate and transfer the methods to one or more FDA field laboratories. With these methods, FDA can rapidly confirm human product label claims for species content by matching short DNA sequences (DNA barcodes) from the products to the DNA sequences in a database of DNA barcodes. DNA barcoding is a unique identifier because it provides a high degree of confidence as to which species is actually present in the food product or sample.

FDA needs to be able to detect mislabeled products, which may occur when material from the labeled species is replaced by material from a substitute species. Species substitution can have a significant impact on human and animal food safety. CVM and FDA’s Center for Food Safety and Nutrition (CFSAN) are collaborating to develop a DNA-based database for species identification. With this database and these methods, FDA will be able to identify products that may pose a threat to human and animal food safety by economic adulteration of food, (i.e., labeling a product as containing material from one species when material from another species has been substituted.) Several molecular assays have been developed and determined suitable for regulatory use and protocols are available to FDA field laboratories. OR tested samples in approximately a dozen regulatory cases during fiscal year 2012.

Biomarker Research

CVM is conducting research to explore whether biomarkers can be used as surrogate measures for drug safety or drug effectiveness in support of the drug approval process. The goal is to develop and validate biomarkers for various applications. These biomarkers may be used by drug sponsors to support their new animal drug applications. These studies use either genomic or proteomic approaches, depending on which type of marker is most appropriate. Studies focused on the development of biomarkers of inflammation that may be used to support the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in food producing animals. We have identified several potential biomarkers of NSAID effectiveness. Future research studies will seek to validate these markers.

CVM Biomarker Discovery. CVM has approved only a limited number of drugs to treat food animals for inflammatory diseases. Approving additional anti-inflammatory drugs could reduce the reliance on antibiotics to treat diseases such as mastitis in dairy cows. Improved criteria are needed to evaluate the effectiveness of such drugs. Proteomic methodologies are being used to evaluate change in bovine milk protein expression following experimental induction of mastitis. The change could be used to evaluate response to anti-inflammatory treatment. Genomics methodologies have also been used to identify biomarkers of inflammation in swine. Three biomarkers have been associated with reduction in signs of inflammation when pigs were administered an NSAID. These three biomarkers will be qualified for use as surrogate endpoints that could be used to evaluate the effectiveness of novel NSAIDs.

Roxarsone Research

Animal drug industry representatives have raised questions regarding the results of an inorganic arsenic tissue residue research study which led to the voluntary removal of the arsenic based drug, roxarsone. In response, CVM developed a scientific strategy aimed at developing additional research to address the scientific issues raised, and to verify the initial study findings. We evaluated the limitations of the initial study and are designing new studies to evaluate our initial findings. A feeding study will determine the stability of roxarsone and its metabolites in tissues collected during drug incursion/depletion studies.

Development of Methods for Detection of Mycotoxins in Animal Feed and Feed Ingredients, Including Distillers Products

In the United States, contamination of crops by mycotoxins occurs widely due to growth of molds in farming and storage. These mycotoxins pose significant threats to animal health when domestic animals eat contaminated feed. Subsequently, if humans consume animal-derived products, they may become sick. We are developing a more efficient analytical method to determine the quantity and confirm the identity of multiple mycotoxins in feed and feed ingredients, especially distillers products.

Distillers products are byproducts of ethanol production. The large increase in fuel ethanol production has resulted in a similar increase in the use of distillers products for animal feed. We do not know if using mycotoxin-contaminated grain to produce ethanol will result in distillers products contaminated with mycotoxin. However, the prospective method will provide the agency with an efficient and sensitive tool for detecting mycotoxins in distillers products and potentially other feed or feed ingredients. The analytical instrument's performance (especially the lower limit of quantitation) was being evaluated at the close of FY 2012. An interim analytical method has been developed which will be thoroughly evaluated and then validated.

(Antibiotic resistance is also a health concern with distillers products. See the section on “Antimicrobial Resistance,” for further discussion).

Detection of Hormones in Meat Products

Identifying hormones used in animal meat production is of interest to CVM, especially those hormones approved in the U.S., but strictly prohibited by the European Union. At the end of the year, CVM scientists had nearly completed developing a single method to detect 16 hormones in beef muscle at part-per-billion detection levels. The draft method has been provided to the USDA Food Safety Inspection Service (FSIS), and is currently being evaluated at FSIS laboratories.

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