Establishing the RTLA Sponsorship and Leadership Growth of the Collection Significant Contributions and Collaborations

Dr. Clyde J. Dawe

Although the cellular proliferative disease known as neoplasia, or cancer, had been recognized in humans and other mammals for thousands of years, the question of whether lower vertebrates and invertebrates might suffer from this disease was not asked until recently. Several discoveries in lower animals by the end of the 19th century and in the early 20th century provided important information that was useful in determining etiologies of human cancers, including gene-dependent neoplasia in the fruitfly, gene-dependent melanoma in platyfish/swordtail hybrids, herpesvirus oncogenicity in leopard frogs, and aflatoxin carcinogenicity in rainbow trout.

Dr. Clyde J. Dawe, a comparative pathologist in the Laboratory of Pathology, Section of Comparative Oncology at the National Cancer Institute (NCI), and others at NCI, questioned whether these and other discoveries might be beneficial in advancing our understanding and treatment of cancer in humans. Studies of neoplasia in lower vertebrates and invertebrates might provide models for human cancers and insights into neoplastic mechanisms, including the influence of genetics and immune mechanisms on tumor induction, identification of oncogenic virus vectors, and evidence of anticancer substances. These organisms might also serve as sentinels for environmental carcinogens and provide cost-effective bioassays for testing carcinogens. Tumor registries for humans and mammals had been established to provide similar information, and were instrumental in advancing the study of neoplasia.

Dr. Dawe assembled an Advisory Committee to discuss the need for a registry of tumors in invertebrate and poikilothermic (cold-blooded) vertebrate animals. Dr. Donald F. Squires, Deputy Director of the Museum of Natural History, Smithsonian Institution and a member of the committee, had discovered this dried skeleton type specimen with an abnormal polyp on the deep-water coral Madrepora kauiensis in the Smithsonian's collection which suggested that even Cnidaria might be susceptible to cellular proliferative disorders. (Although this lesion was later shown to be caused by a parasitic ascothoracid crab, other skeletal anomalies of corals are arguably neoplastic, such as the one later identified by Dr. Dawe and Dr. Esther C. Peters as a calicoblastic epithelioma affecting acroporid corals.)

Dr. Dawe's proposed Registry of Tumors in Lower Animals (RTLA) was endorsed by the National Academy of Sciences Subcommittee on Comparative Pathology and established in 1965 by Dr. Dawe and Dr. Mearl F. Stanton, a member of the Laboratory of Pathology, Section on Cancer Induction and Pathogenesis at the NCI. Among the first accessions were 17 specimens contributed from their personal collections.

The RTLA had been funded by the National Cancer Institute (NCI), U.S. National Institutes of Health (NIH), from July 1966, until September 30, 2007.

The RTLA contract was initially awarded to the Smithsonian Institution, Washington, DC, to continue the project. Dr. Dawe served as NCI Project Officer and Dr. Squires was the Smithsonian's Principal Investigator. The facility was established in the National Museum of Natural History. Dr. George E. Cantwell, who was studying the effects of mammalian chemical carcinogens on invertebrates at the U.S. Department of Agriculture, took a year's leave of absence to become the Registry's first Director in September 1966. Dr. John C. Harshbarger became the Principal Investigator and Director in 1967. In 1995, the RTLA was relocated to the Department of Pathology, The George Washington University Medical Center, Washington, DC.

In September 2002 until September 2007, the RTLA contract was awarded by NCI to Experimental Pathology Laboratories, Inc. (EPL), in Sterling, Virginia, approximately 25 miles west of Washington, DC, near Dulles International Airport. Mr. Phil Daschner was the Project Officer and Ms. Ellen Zaika was the Co-Project Officer during this time period.

From its inception, the RTLA has been a repository for diverse materials pertaining to the study and documentation of neoplasia and related diseases in cold-blooded vertebrates and invertebrates, i.e., all animal groups except mammals and birds. The archived collection contains whole animals and tissues in fixative or preservative solutions, stained and unstained sections on microscope slides, paraffin and plastic blocks, photographs, collection data, necropsy reports, and pertinent scientific literature. Information and data on each accession is entered into the RTLA database to document factors that might be associated with the diseased state of the organism. Some normal specimens of the same species from the same site as diseased specimens have also been contributed for comparison. The RTLA has provided diagnostic services, as well as interacted with other comparative pathologists to distinguish difficult cases. As a central repository offering services and resources to all who are interested in the study of neoplasia in reptiles, amphibians, fishes, and invertebrates, the RTLA has proven invaluable.

The collection currently contains more than 7,700 accessions, and more than 7,400 associated scientific articles. The distribution of accessions by class is shown in this figure. Bony fishes represent 64% of the cases from 10 phyla and 32 classes in the collection. About 50% of the cases are animals with neoplastic lesions; the remaining cases have developmental, parasitic, infectious, toxic, traumatic, or other types of lesions.

The RTLA has also archived several important collections of diseased lower animals, including Lucké renal adenocarcinomas in leopard frogs contributed by Dr. William R. Duryee, tumors affecting fruitflies contributed by Dr. Mary B. Stark, viruses of blue crabs contributed by Dr. Phyllis T. Johnson, and the Registry of Marine Pathology, which was originally developed by Dr. Aaron Rosenfield of the National Marine Fisheries Service's laboratory in Oxford, Maryland. In July 2003, the U.S. Army Center for Environmental Health Research contributed pathology slides from toxicologic studies of fish, mainly medaka.

The RTLA has sponsored seminars and workshops on neoplastic and non-neoplastic conditions of lower animals in various venues, as well as sessions at national and international professional society and other meetings. The RTLA participates in many professional activities and collaborations with scientific investigators around the world.

One of the first projects supported by the National Research Council's Committee on Pathology was "A Symposium on Neoplasms and Related Disorders of Invertebrate and Lower Vertebrate Animals," which was held at the Smithsonian Institution, Washington, DC, June 19-21, 1968 (proceedings published July 1969, National Cancer Institute Monograph 31, Bethesda, Maryland, edited by Drs. Clyde J. Dawe and John C. Harshbarger).

The symposium on "Use of Small Fish Species in Carcinogenicity Testing" was held December 8-10, 1981, at the Lister Hill Center on the campus of the National Institutes of Health, Bethesda, Maryland (proceedings published May 1984, National Cancer Institute Monograph 65, NIH Publication No. 84-2653, U.S. Dept. Health and Human Services, Public Health Service, NIH Bethesda, Maryland, edited by Dr. Karen L. Hoover).

Dr. Harshbarger was the first recipient of the "Prince Hitachi Prize for Comparative Oncology," presented by H.I.H. Prince Hitachi on May 27, 1996, in Tokyo, Japan. Among many other scientific and professional honors, he was also awarded the U.S. Environmental Protection Agency's (EPA) Scientific and Technological Achievement Award, Level II, for the publication "Carcinogenicity of Black Rock Harbor Carcinogens from the Blue Mussel to the Winter Flounder," co-authored with EPA scientists on October 5, 1993.

Dr. Harshbarger and several fisheries scientists and fish pathologists offered testimony during a hearing on September 21, 1983, before the Subcommittee on Merchant Marine Fisheries and the Environment of the Committee on Merchant Marine and Fisheries in the House of Representatives, 98th Congress. The topic of this hearing was "The Causes of Reported Epidemics of Cancer in Fish and the Relationship Between These Occurrences and Environmental Quality and Human Health."

In addition to providing information to biologists, veterinarians, physicians, students, media, government officials, and others, the RTLA database can be used to identify clusters of cancers, as well as their significance. The RTLA's Principal Investigators have been available to assist in research on neoplasms and related disorders, offering expertise, contacts, resources, and materials for these studies. Examples of these collaborations include the following:

•  Cellular proliferative diseases of the thyroid in fishes (with Dr. John Fournie, U.S. Environmental Protection Agency, Gulf Ecology Division, Gulf Breeze, Florida).
  
  
•  Shark cartilage available for the treatment of cancer as an angiogenesis inhibitor (with Dr. Gary Ostrander, Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland and others).
  
  
•  Zebrafish (Danio rerio) as a model of human neoplasia (with Dr. Keith Cheng and colleagues, The Jake Gittlen Cancer Research Institute, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania).
  
  
•  Investigation of zooplankton cancer reported in Science (with Dr. Gretchen Messick, Center for Coastal Environmental Health and Biomedical Research, Cooperative Oxford Laboratory, Oxford, Maryland; Dr. Henry Vanderploeg, Great Lakes Environmental Research Laboratory, National Oceanic and Atmospheric Administration, Ann Arbor, Michigan; Mr. M. Omair, Division of Biological Sciences, University of Michigan, Ann Arbor, Michigan; and Dr. Arthur Chiu, National Center for Environmental Assessment; U.S. Environmental Protection Agency, Washington, DC).
  
  
•  Cancer histopathology of brown bullhead catfish (Ameiurus nebulosus) from several sites in the tidal Potomac River watershed including the Anacostia River, Washington, DC (with Dr. Alfred Pinkney, Chesapeake Field Office, U.S. Fish and Wildlife Service, Annapolis, Maryland; and Dr. Eric May, Maryland Fish and Wildlife Cooperative Unit, University of Maryland Eastern Shore, Princess Anne, Maryland).
  
  
•  Epizootic fibrous tumors in endangered marine turtles (with Mr. George Balazs, Leader, Marine Turtle Research Program, National Marine Fisheries Service, Honolulu, Hawaii; Dr. Llewellyn Ehrhart, Department of Biology, University of Central Florida, Orlando, Florida; Dr. Ernest Williams, Jr., Department of Marine Sciences, University of Puerto Rico, Lajas, Puerto Rico; and Dr. Barbara Schroeder, National Marine Fisheries Service, Silver Spring, Maryland; and others).
  
  
•  Cancer histopathology of catfish collected at an inactive coking plant outfall on the Black River, Lorain, Ohio, and reference site, Old Woman Creek National Estuary, Huron, Ohio, to assess the rate of natural remediation and the impact of any reactivation of the plant (with Dr. Paul Baumann, National Biological Service, U.S. Geological Survey, U.S. Department of the Interior, Ohio State University, Columbus, Ohio).

We have made this history short and succinct for our web readers; however, the RTLA has had a richer and more productive role in our understanding of cancer than can be conveyed in this limited space.