ORNL's biological research program was established to determine the nature and effects of radiation on living cells. These studies were motivated by concerns about health effects of radiation from reactors, atomic weapons testing, and radioactive elements that enter the body.
Alexander Hollaender, a world authority in radiation biology, came to Oak Ridge in 1946 to lead studies on the effects of radiation on microorganisms, fruit flies, plants, and later mice. He built a broad program that once gave ORNL the largest biological laboratory in the world. Twenty researchers who have worked in the biological sciences at ORNL have been elected to the National Academy of Sciences.
Under Hollaender, Bill and Liane Russell started a large-scale mouse-genetics project in 1947. They began to build up special mouse strains for study of the effects on offspring born to parents exposed to radiation. The mouse-genetics program eventually would accommodate a steady-state census of 250,000 mice.
The Russells also initiated a project to study radiation effects on development. In 1950, Liane Russell reported that specific types of birth defects resulted from radiation exposure during "critical periods" in embryonic development. In 1952, the Russells jointly informed the medical community that the stage of prenatal development at which radiation is introduced strongly influences the amount and type of damage to the human embryo and fetus. They made specific recommendations on avoiding risks to unsuspected human pregnancies from diagnostic X rays that were adopted worldwide.
Gene Oakberg's studies of mouse development have helped biologists worldwide interpret the genetic effects of mutagens. ORNL's radiation-mutagenesis studies had generated so many findings by 1956 that a National Academy of Sciences committee used these mouse data to formulate projections for the genetic effects of radiation in humans. National and international bodies continued to rely on ORNL data on the effects of biological and physical variables on mutation rates in recommending limits for human radiation exposures.
Also in 1956, Takashi Makinodan used high radiation doses to suppress mouse immune systems by destroying certain blood cells and then performed the world's first successful transplants of bone marrow (from rats into mice). That same year Elliott Volkin and Larry Astrachan discovered messenger RNA, which "reads" DNA's genetic code and becomes a template for mass-producing proteins. Nine years earlier, Volkin and Waldo Cohn observed that RNA (ribonucleic acid) has the same general structure as DNA (deoxyribonucleic acid), a discovery that had a fundamental impact on molecular biology, virology, and genetics.
In 1958 Bill Russell and colleagues demonstrated that spreading a given radiation dose over days or weeks produced fewer mutations in mice than administering the same amount of radiation within minutes. This provided the first evidence that DNA damage that would result in mutations can be repaired. The finding also had implications for permissible exposure levels.
In 1959 Liane Russell and colleagues found that maleness in the mouse depends on the presence of the Y chromosome and is unrelated to the number of X chromosomes. A year later she showed that only one of the two X chromosomes of a mammalian female is active.
In the mid-1960s, ORNL biologists began measuring the genetic effects of chemicals, using several methods that had been developed for research on radiation effects. The National Cancer Institute supported ORNL investigations of the complex biochemical events leading to cancer growth in mice exposed to radiation or chemicals. Arthur Upton (who later became NCI director), John Storer, and others conducted experiments to determine whether lung cancer tumors in mice form as a result of exposure to pesticides, sulfur dioxide, city smog, or cigarette smoke, both singly and together.
In 1967, Oscar Miller and Barbara Beatty placed frog eggs under a high-resolution experimental microscope built at ORNL and photographed genes in the act of making RNA. The journal Cell Biology named the resulting paper a landmark publication.
In 1972 ORNL's Peter Mazur and Stanley Leibo (with England's David Whittingham) froze, thawed, and implanted mouse embryos in surrogate mothers that gave birth to healthy mouse pups. The technique, featured on the cover of Science magazine, was adopted by the cattle industry for multiplying the reproductive potential of prize cattle. The embryo cryopreservation technique, used in Oak Ridge and at the Jackson Laboratory in Bar Harbor, Maine, allows the affordable maintenance of genetic lines of mice and provides a method for obtaining virus-free lines of mice with known genetic traits.
In 1979, Willie Lijinsky showed in rats that nitrites from food preservatives react with amines from food and drugs to form cancer-causing nitrosamines during digestion in the stomach. Walderico Generoso discovered that the genetic makeup of the unexposed female mouse is critically important for determining the amount of genetic damage passed to offspring by males exposed to certain chemicals. Bill Russell discovered that ethylnitrosourea (ENU) is the most effective chemical for inducing mutations in mice. Subsequently, it was found that this chemical generates primarily "point" mutations (DNA base substitutions rather than deletions), and ENU is now in widespread use as the gold-standard reagent for the discovery and cloning of genes associated with human diseases.
In 1986 Generoso discovered that exposure of newly fertilized mouse embryos within the mother to certain chemicals increases the possibility of specific late-fetal birth defects. This work upset teratology dogma that exposure only during the formation and development of organs poses a significant risk.
By the 1990s, numerous studies led by Liane Russell on the nature and frequency of chemically induced mutations concluded that germ-cell-stage exposure to a mutagen is more important than the mutagen itself in determining the nature of a heritable mutation. Thus, it was possible to find suitable chemicals and exposure protocols for making certain classes of mutations "to order."
In 1992 Scott Bultman, Ed Michaud, and Rick Woychik identified and cloned the mouse agouti gene, which causes altered fur color, obesity, diabetes, and cancer in mice and has a human counterpart. In 1993 Gene Rinchik helped identify the human and mouse pink-eyed dilution gene that enables normal pigmentation in mammals. In 1994, using mice, Woychik and his associates generated an insertional mutation exhibiting polycystic kidney disease and identified the gene responsible.
In 1995 Cymbeline Culiat and Rinchik demonstrated that deficiency of a neurotransmitter receptor leads to cleft palate in mice, resulting in tests by human geneticists. Gerald Bunick produced the seeds of DNA-protein crystals that were grown in space aboard the space shuttle and an orbiting space station.
In 1998 Audrey Stevens was elected to the National Academy of Sciences for her successes in identifying numerous proteins involved in RNA metabolism. In 2001 Dabney Johnson, Culiat, and Rinchik proved they had developed mouse models for the acute and the chronic forms of the human disease hereditary tyrosinemia, enabling laboratory tests that might lead to therapies.
Today ORNL biologists are looking forward to conducting research at the new Mouse House, scheduled to open in July 2003, to further advance the field of mammalian genetics.
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