H.J. Muller's contributions to mutation research.

H. J. Muller is best known for his Nobel Prize work on the induction of mutations by ionizing radiation. Geneticists are less familiar with his contributions to mutation and how he related the process of mutagenesis to the gene and distinguished gene mutations from other genetic and epigenetic events such as polyploidy, chromosome rearrangements, and position effects. The hallmark of Muller's contributions is his design of genetic stocks to solve genetic problems and allow experimentation to reveal new phenomena. In this review I relate Muller's personality to his teaching and research and present a history of Muller's ideas on mutation from his first days in Morgan's fly lab to his final thoughts on what became called "Muller's ratchet", a term he did not get to enjoy because it was coined seven years after his death.

A glance into how the cold war and governmental loyalty investigations came to affect a leading U.S. radiation geneticist: Lewis J. Stadler's nightmare.

This paper describes an episode in the life of the prominent plant radiation geneticist, Lewis J. Stadler (1897-1954) during which he became a target of the Federal Bureau of Investigation (FBI) concerning loyalty to the United States due to possible associations with the communist party. The research is based on considerable private correspondence of Dr. Stadler, the FBI interrogatory questions and Dr. Stadler's answers and letters of support for Dr. Stadler by leading scientists such as, Hermann J. Muller.

James V. Neel and Yuri E. Dubrova: Cold War debates and the genetic effects of low-dose radiation.

This article traces disagreements about the genetic effects of low-dose radiation exposure as waged by James Neel (1915-2000), a central figure in radiation studies of Japanese populations after World War II, and Yuri Dubrova (1955-), who analyzed the 1986 Chernobyl nuclear power plant accident. In a 1996 article in Nature, Dubrova reported a statistically significant increase in the minisatellite (junk) DNA mutation rate in the children of parents who received a high dose of radiation from the Chernobyl accident, contradicting studies that found no significant inherited genetic effects among offspring of Japanese A-bomb survivors. Neel's subsequent defense of his large-scale longitudinal studies of the genetic effects of ionizing radiation consolidated current scientific understandings of low-dose ionizing radiation. The article seeks to explain how the Hiroshima/Nagasaki data remain hegemonic in radiation studies, contextualizing the debate with attention to the perceived inferiority of Soviet genetic science during the Cold War.

Failla Memorial Lecture. From beans to genes--back to the future.

Developments in radiation biology have inevitably paralleled the evolution of systems and end points in the wider field of biology. I review the development of three areas that have interested me during the 35 years that I have been involved with radiation research. (1) The dose-rate effect. My first graduate student, Joel Bedford, and I demonstrated the dependence of mammalian cell killing on the dose rate at which gamma rays are delivered. These studies led to the recent development of pulsed low-dose-rate brachytherapy and the design of a new machine for clinical use. (2) Hypoxic radiosensitizers and bioreductive drugs. The hypothesis that the presence of foci of hypoxic cells in human tumors could limit their curability by gamma rays led to the development of nitromidazales that preferentially sensitize hypoxic cells. Our contributions included the observation that misonidazole was also cytotoxic to hypoxic cells, that sensitization was increased by prolonged preincubation, and that the mechanism involved depletion of thiols. More recently we have collaborated with Ged Adams and Bob Sutherland in the development of a new generation of hypoxic cell cytotoxins. In particular, we have been concerned with the assessment of oncogenicity in relation to drug structure. (3) Oncogenic transformation in vitro. The use of in vitro assays for oncogenic transformation has represented a major interest for this laboratory largely due to collaborations first with Carmia Borek, and more recently with Richard Miller and Tom Hei. We published the first dose-response curves for gamma rays, and more recently for a range of neutron energies and for charged particles of defined LET. Radiation-induced oncogenic transformation in C3H 10T1/2 cells has been shown to be due to a dominant acting transforming gene, which has been isolated and is in the process of being characterized and sequenced by Greg Freyer.

Radiation Research Society. 1952-2002. Historical and current highlights in radiation biology: has anything important been learned by irradiating cells?

Around 30 years ago, a very prominent molecular biologist confidently proclaimed that nothing of fundamental importance has ever been learned by irradiating cells! The poor man obviously did not know about discoveries such as DNA repair, mutagenesis, connections between mutagenesis and carcinogenesis, genomic instability, transposable genetic elements, cell cycle checkpoints, or lines of evidence historically linking the genetic material with nucleic acids, or origins of the subject of oxidative stress in organisms, to name a few things of fundamental importance learned by irradiating cells that were well known even at that time. Early radiation studies were, quite naturally, phenomenological. They led to the realization that radiations could cause pronounced biological effects. This was followed by an accelerating expansion of investigations of the nature of these radiobiological phenomena, the beginnings of studies aimed toward better understanding the underlying mechanisms, and a better appreciation of the far-reaching implications for biology, and for society in general. Areas of principal importance included acute tissue and tumor responses for applications in medicine, whole-body radiation effects in plants and animals, radiation genetics and cytogenetics, mutagenesis, carcinogenesis, cellular radiation responses including cell reproductive death, cell cycle effects and checkpoint responses, underlying molecular targets leading to biological effects, DNA repair, and the genetic control of radiosensitivity. This review summarizes some of the highlights in these areas, and points to numerous examples where indeed, many things of considerable fundamental importance have been learned by irradiating cells.

Reminiscences of a mouse specific-locus test addict.

This paper describes some of the historical events surrounding the development of and achievements with the mouse specific-locus test in radiation and chemical mutagenesis. Some ongoing and future contributions of the test to research in molecular genetics are also mentioned.

James Neel and the doubling dose concept.

The doubling dose (DD) is a very valuable concept in attempts to assess the genetic risks of radiation in man. It was long thought that the value of the doubling dose obtained from specific locus experiments in mice could be applied to man. James Neel, as a result of his studies on the offspring of atomic bomb survivors, showed that this was not so, but that different doubling doses could be inferred from different endpoints.