How did radioactivity go from a scientist’s toy to a key tool in life sciences research?

The dangers of radioactivity to living things were not well understood in the past, but Hermann Joseph Muller’s discovery that radioactivity causes mutations turned it into an important tool for life science research.

 

Radioactivity is dangerous. After the Fukushima disaster, radioactivity made Japanese seafood disappear from the table, and people became reluctant to have nuclear power plants and radioactive waste disposal facilities near their homes. Chernobyl, a sleepy town in Belarus, remains a no-man’s land. But the effects of radioactivity on living things, which killed two-time Nobel Prize winner Marie Curie, workers at a factory making fluorescent clocks (aka the “radium girls”), and countless others too numerous to mention, were surprisingly poorly understood until the early 20th century. It was thanks to Hermann Joseph Muller that radioactivity was transformed from a plaything of physicists to an important object of study in the life sciences. He helped us understand how radioactivity affects life and, more importantly, how it could be used in life science research.
Hermann Joseph Muller’s most outstanding scientific achievement was his paper “The Problem of Genetic Modification,” published in 1927 at the International Congress of Genetics (ICG) in Berlin, in which he demonstrated that radioactivity causes mutations in the DNA of fruit flies. To understand this method, we first need to know about the ClB chromosome, an important device used in the experiment.
After observing a large number of fruit flies and their offspring, Muller obtained a fruit fly with a specialized X chromosome that had several important mutations. This chromosome had three main abnormalities compared to normal fruit flies. The first mutation was in an important gene that is essential for life. If both X chromosomes in the female had this mutation, or if the only X chromosome in the male had this mutation (males have one X and one Y chromosome), the fruit fly would die before birth. However, if only one X chromosome in the female has the mutation, the fruit fly can live. This mutation is called a recessive lethal gene because it doesn’t function when paired with a normal gene. The second mutation was in a gene that determines the shape of the eye. If you have one of these mutations, your eyes will be flatter instead of round. The last mutation was in a gene that helps chromosomes mix during egg production. Genetic diversity is an important factor in the longevity of a species, and multicellular organisms, including humans and fruit flies, achieve genetic diversity by mixing chromosomes from their parents through a process called crossover. But this mutation prevents crossover from occurring in fruit fly cells. This prevents the chromosomes that Muller discovered from being destroyed in the crossing over process. The chromosome is called the ClB chromosome, after the first letter of each mutation’s English name (Cross-compressor, lethal, Bar-eye).
Muller’s paper used this unusual and cleverly constructed chromosome to demonstrate that radiation can create unintended mutations. The experiment was simple. First, healthy males without the mutation were mated to females with one of their two X chromosomes being a ClB chromosome (females cannot survive if both are ClB). The females did not have the lethal gene on their father’s X chromosome, so they were able to survive even though they had inherited the ClB chromosome from their mother. The probability of receiving either a normal chromosome or a ClB chromosome is exactly 1/2, so the females with the rod-shaped eyes would make up half of all the new female fruit flies. Next, the males were exposed to different intensities of X-rays before the experiment, and then the same experiment was performed. Surprisingly, the stronger the X-ray exposure, the lower the percentage of young female fruit flies with rod-shaped eyes.
Muller interpreted this to mean that the X-rays caused a recessive lethal gene mutation in the father fruit fly’s normal X chromosome. If X-rays create a recessive lethal gene on the X chromosome of the father fruit fly, the stick-eyed fruit flies that receive the ClB chromosome from the mother and the recessive lethal gene from the father cannot survive. However, if the fruit fly receives a normal X chromosome from its mother, it can be born normally, even if it has a recessive lethal mutation on its father’s X chromosome. Thus, Muller’s interpretation correctly explains why the number of fruit flies with normal eyes remained almost unchanged, but the number of fruit flies with rod-shaped eyes decreased. This proved that X-rays cause mutations.
Muller’s work revolutionized biology. Mutations are the most basic tool for studying DNA, and the easiest way to figure out what a particular section of DNA does is to compare individuals with mutations in that section. In fact, both Mendel’s pea experiment and Muller’s mentor Morgan’s experiments utilized naturally occurring mutations.
However, naturally occurring mutations are very rare. In fruit flies, one in about 360 million base pairs of DNA is mutated every time it is replicated. If we take the size of a typical gene to be 1600 base pairs (based on human hemoglobin), only about one in 220,000 individuals will have a mutation in the gene we want. But not all mutations affect the phenotype, so the odds of getting the mutant we want are even lower. After more than two years of experimentation, Morgan was able to find a fruit fly with white eyes. Considering that a generation of fruit flies lasts about two weeks, using natural mutations for research was very laborious.
Muller’s method, on the other hand, allowed biologists to dramatically shorten the experimental time. By using radioactivity to artificially increase the mutation rate, it becomes easier to find individuals with mutations in the desired DNA segment. Many early genetics experiments, including Beadle and Tatum’s one-gene-one-effector experiment, utilized radioactive mutagenesis, which contributed significantly to the development of genetics.
After his fruit fly experiments, Muller continued to experiment with other species, including corn, wasps, and other mutagens, such as mustard gas. He also warned of the dangers of mutagens to humans in his 1941 paper “Role of Radiation Mutations in Mankind” and other articles. In 1946, the year after two atomic bombs were dropped on Japan, Muller was awarded the Nobel Prize.
Muller’s work contributed to many monumental experiments in biology, as discussed above. Today, of course, radioactivity is rarely used in biology experiments, thanks to new technologies like restriction enzymes and TALEN/Crispr-Cas9 gene scissors that allow us to precisely cut and paste specific sections of DNA. But it’s still important because it dramatically improved the efficiency of mutation research, which relied on extremely low probabilities.