Strange Glow

by Timothy J Jorgensen

  An enormous monkey study was quickly ruled infeasible for a variety of practical reasons, so mice, once again, became the only option. It was decided that another mouse study, even larger than the Rochester study, with irradiation conditions that more closely mimicked human exposure conditions could settle the question. With this, the megamouse project was conceived.41 It would ultimately be conducted at Oak Ridge National Laboratories in Tennessee, by Liane B. Russell and William L. Russell and would involve 7,000,000 mice (nearly the current human population of New York City); this was a mouse study that would be almost 100 times larger than the human LSS.

  It took 10 years to complete the megamouse project, and the LSS is still ongoing. True to prediction, the LSS never found a significant increase in inheritable mutations. The mouse study, however, did show a significant increase, but it was only twofold, as opposed to the ninefold increase seen in the Rochester mouse study. Why the difference?

  For the most part, the Oak Ridge findings agreed with the earlier Rochester work, but a few very key additional facts emerged that greatly lowered the anxiety level. First, researchers found that by lowering the dose rate to which the mice were exposed from 900 mSv per minute (the Rochester dose rate) to 8 mSv per minute (i.e., much closer to the dose rates that radiation workers would actually experience), the mutation rates dropped dramatically.42 Second, if the male mice were not immediately mated with the females following irradiation, the mutation rate also dropped precipitously. The longer the time between irradiation and mating, the lower the mutation rate. Some reduction in mutation rate could be seen if mating was delayed even a few days, but the rate continued to drop even up to a two-month period after irradiation. The likely explanation was that newly produced sperm replenishes the radiation-damaged sperm during this delay period, so that nearly all the damaged sperm had been replaced two months after irradiation. Also, postirradiation cellular repair processes probably mitigated the mutation production when dose rates were lower and conception times delayed.

  Of the two modifying factors—dose rate and postirradiation conception interval—the lower dose rate was the more important factor in mitigating inheritable mutation risk in a radiation worker setting. Based on the new mouse data collected at the lower dose rate, it was determined that it would take a dose as high as 1,000 mSv to double the natural background rate of inheritable mutations, rather than just the 80 mSv suggested by the Rochester high dose-rate experiments. Also, although the time between radiation exposure and conception could not be controlled among humans, the reality is that very few of a male worker’s offspring would be conceived immediately following a relatively high dose exposure to his genitals, whereas all of the mice in the Rochester study were conceived immediately following irradiation. This, too, was a factor that would significantly suppress the actual inheritable mutation rates in humans in real-life exposure situations. Thus, these new findings in mice did much to relieve the tremendous anxiety caused by the earlier fruit fly studies.

  In the end, the only useful data for setting radiation protection standards for inheritable mutations came from the positive mouse studies and the one negative human study. Even though negative, the LSS’s findings suggested that human sensitivity to radiation was not significantly higher than the sensitivity of mice, and that dose limits set to protect against inheritable mutations could be set based on the mouse data.

  Ironically, identification of the exact dose limits for protection against inheritable mutations became a moot point. This is because human sensitivity to radiation-induced inheritable mutation turned out to be much lower than human sensitivity to radiation-induced cancer. So the dose-limiting factor for human protection standards came to be the cancer health effect and not the inheritable mutation effect. In other words, the dose limits set to protect against radiation-induced cancer more than adequately protect against the inheritable mutation hazard. In protecting against cancer, you protect against both.

  Some people couldn’t accept that it wasn’t possible to find significant numbers of mutants among the atomic bomb survivors. After all, there were birth defects among the children of pregnant women exposed to bomb radiation (primarily small head sizes and mental deficiencies). Weren’t they mutants?

  No, they weren’t. It is important to understand that not all children with birth defects represent new inheritable mutants. In fact, very few do. And this is particularly true for children who are born with defects because they were exposed to high doses of radiation while in the womb. When doses get high enough to cause cell death (~1,000 mSv), they can cause radiation sickness in adults due to the killing of cells in critical tissues, but they can also cause birth defects by killing off cells in critical tissues that are growing and developing within embryos. This can be thought of as a type of radiation sickness of embryos. Because there are many different types of developing tissues in embryos, each of which becomes relatively sensitive at different times during gestation, various types of birth defects can appear following irradiation of pregnant women. The major determinant of exactly which type of birth defect will arise is the specific day of gestation when the irradiation occurred. But the children born with these defects do not ordinarily have any genetic defects that would affect their fertility, reproduction rate, or mutation rate, because they are not genetic mutants (i.e., their deformity is not inheritable). This distinction is often misunderstood.

  The bottom line is, once again, that high radiation doses kill dividing cells wherever they might be found, whether in the bone marrow of adults (producing anemia), the intestinal lining (producing GI breakdown), the developing embryo (producing birth defects), or the testicle (producing low sperm counts or sterility). These health effects, in and of themselves, are not evidence of gene mutations; rather, mutations happen through a different process that typically does not involve cell death because dead cells cannot pass on their genes.

  Testicular irradiation and effects on sperm production have been an unfortunate recurring theme in this book, with no mention at all about female ovaries and the effect of radiation on their eggs. This is because less was originally known about radiation effects on eggs, since it was much easier to get postirradiation sperm counts from men than egg counts from women. Nevertheless, we now know a good deal about how radiation affects the ovaries and eggs, and it seems that women get the worst of it.43

  The reason has to do with the way a woman’s eggs are produced. Sperm are produced continuously throughout a man’s life by the spermatogonia cells in the testicles. Eggs, in contrast, are produced only during embryonic development, so that a woman has all the eggs for her entire lifetime on the day she is born. With time these eggs either ovulate individually during the menstrual cycle and find their way through the fallopian tubes to the uterus, or they randomly die off as they age (the fate of most eggs) until they are all gone at around age 55. Since production of the female hormone estrogen in the ovaries is dependent upon the presence of viable eggs, the complete loss of eggs means the loss of estrogen, and menopause ensues.

  By killing off eggs, radiation hastens the day when the eggs will be completely gone, and thus produces premature menopause. In contrast, production of the male hormone testosterone in the testicles is not dependent upon the presence of viable sperm, so even complete and permanent sterilization of men with radiation does not eliminate testosterone production. Thus, radiation sterilization of women is the equivalent of female castration (i.e., removal of the ovaries) since both eggs and hormones are gone; but sterilization of men with radiation is not the equivalent of male castration (i.e., removal of the testicles), because the male hormone levels and libido remain normal, and primary and secondary sex characteristics are retained.

  Science can sometimes be a self-corrupting process. In an attempt to give relevance to research that outsiders often perceive as arcane, scientists at times resort to public rhetoric. Repeated enough, scientists can begin to believe their own rhetoric, and that rhetoric then starts driving the d
irection of the science, rather than the science driving the rhetoric.

  Muller had wallowed in his share of rhetoric, but he rose to his very best when he stuck with the science. That was his training and where his genius lay. He had recognized the reasons why fruit fly mutants were so hard to measure, and he had the brilliance to circumvent the problem with his X-linked lethal mutation assay. Muller later realized the newly identified viruses that could infect bacteria (bacteriophages) would provide a revolutionary new tool for taking genetics to its next frontier; this was the means to discover the stuff of genes. Such viruses behave like autonomous genes that move around independently through the environment, unencumbered by any cellular milieu, and then suddenly infect bacterial cells, hijacking those cells’ internal machinery for viral gene reproduction. Like genes, viruses can also be mutated. Muller recognized that the supremacy of the fruit fly in genetic research was coming to an end, and he ventured to predict the new direction that experimental genetics would take:

  [Viruses provide] an utterly new angle [from which] to attack the gene problem. They are filterable, to some extent isolatable, can be handled in test tubes, and their properties, as shown by their effect on the bacteria, can be studied after treatment. It would be very rash to call these [viruses] genes, and yet at present we must confess that there is no distinction known between genes and them. Hence, we cannot categorically deny that perhaps we may [soon] be able to grind genes in a mortar and cook them in a beaker after all. Must we geneticists become … chemists … simultaneous[ly] with being zoologists and botanists? Let’s hope so.44

  Of all Muller’s predictions, this was the most prescient. In this prophecy, at least, he would prove to be absolutely correct.

  Muller also provided another major scientific contribution to radiation protection in that he made people rethink the concept of a tolerance dose—the longstanding idea that for every health effect of radiation there existed some dose below which there was absolutely no risk at all. We now know that this concept is applicable only to radiation effects where the health consequence is a result of killing cells. When doses aren’t high enough to kill cells (i.e., greater than ~1,000 mSv), there can be no such health effect. In contrast, for inheritable mutations (and cancer), where cell death does not drive the health effect, the tolerance dose concept is meaningless. This is because, for the lower-dose health effects, risk is determined by the probability of damaging a specific biological target within a viable cell, a matter that we will deal with presently.

  Muller remained committed to teaching the next generation of geneticists up until his retirement. He taught an annual course called Mutation and the Gene, which was very popular among biology students at Indiana University. Muller remembered one lanky young man in particular as being the brightest student he ever had, but also recalled him as having a nervous disposition and some difficulty with orally expressing his ideas.45 Remarkably, in less than five years, that inarticulate student would coauthor a paper that would rock the entire world of biology, and give the work of Mendel, Morgan, and even Muller himself, an entirely new perspective. The young man was James D. Watson, and his revolutionary discovery, in 1953, pushed fruit fly genetics off center stage and provided new insight into fundamental genetic questions that Muller could only dream about. It would also help reveal the still unknown mechanism by which radiation produces its biological effects.46

  CHAPTER 11

  CRYSTAL CLEAR: THE TARGET FOR RADIATION DAMAGE

  At once I felt something was not right. I could not pinpoint the mistake, however, until I looked at the illustrations for several minutes. Then I realized that the phosphate groups in [Linus Pauling’s] model were not ionized. … Pauling’s nucleic acid in a sense was not an acid at all … a giant had forgotten elementary college chemistry!

  —James D. Watson

  A scientist will never show any kindness for a theory which he did not start himself.

  —Mark Twain

  THE RED BADGE OF COURAGE

  It is a common misconception that James Watson and Francis Crick discovered DNA. They did not. What they discovered was the structure of DNA, and the structure they identified revolutionized the way we now think about genetics. But if you’ve never heard of Watson, Crick, or even DNA, never mind. We’re getting way ahead of ourselves. Let’s put DNA aside for the moment. Our story of the cellular target for radiation damage doesn’t start with DNA. Rather, it starts with pus.

  Pus is that thick, yellowish stuff that oozes from infected wounds and soaks bandages. It is composed largely of white blood cells called leukocytes (from the Greek leukos, meaning white), which are in the process of attacking microscopic foreign invaders, be they bacteria, viruses, or yeast. In the zeal of battle, leukocytes swarm through the blood stream to the site of infection, reproducing wildly to spawn their own replacements, often bloating the area with their sheer numbers and leaking out of every orifice of the wound.

  It was 1869, just four years after Mendel had published his seminal work on the genetics of peas, when Johannes Friedrich Miescher (1844–1895) began to study the chemical composition of human leukocytes.1 Miescher had just graduated from Basel University Medical School in Switzerland, but was unenthused about becoming a practicing physician. His uncle Wilhelm His was a prominent physiologist on the medical school’s faculty, who had made major contributions toward understanding the embryonic development of the nervous system. His suggested to Miescher that he might pursue a career in biological research as an alternative to practicing medicine, and further expressed to his young nephew his conviction that the key to understanding biology lay in determining the chemical composition of cells. Miescher admired his uncle’s wisdom and resolved to devote himself to investigating the chemistry of cells. He moved to the nearby city of Tübingen, Germany, a center for scientific research at the time, and started working in the laboratory of Adolf Strecker (1822–1871), an organic chemist internationally recognized for being the first person to artificially synthesize an amino acid (alanine). Amino acids are the molecular links (monomers) that join with each other to form long-chained molecules (polymers) known as proteins. In their various forms, proteins are the major structural and regulatory molecules of all cells and tissues. Thus, Strecker had synthesized what was essentially a building block of life. Miescher had chosen wisely in deciding to work with Strecker and learned much chemistry from him.

  After a while, however, Miescher became bored with the drudgery of amino acid syntheses. He began to believe that proteins themselves, rather than their amino acid building blocks, hold the key to life’s secrets. So he left Strecker and started working with Felix Hoppe-Seyler (1825–1895), a pioneer in the new field of biochemistry. Hoppe-Seyler was among the first to directly study proteins, and had actually coined the term from the Greek proteios, meaning “the primary or main thing.” Thus, by its very name, protein claimed preeminence among biological molecules.

  Miescher reasoned that the most basic chemical constituents required for life would most easily be isolated from the most basic of cell types. Since leukocytes are among the smallest and simplest of all known human cells, he decided to work with them. Leukocytes tend to congregate in lymph nodes, those small olive-shaped immune glands found in the groin, armpits, and neck. Miescher recruited volunteers and tried to extract leukocytes from their lymph nodes with syringes, but he could never get quite enough for his needs. Then he had a brainstorm. Pus from wounds was laden with leukocytes. He decided to collect fresh bandage waste from hospitals and scrape off the pus to get his leukocytes.

  With leukocytes now in hand, Miescher first developed methods to wash them free of debris. Then he designed techniques to separate their protein from their lipids (i.e., fat), the other main chemical constituent of cells. During these procedures Miescher identified yet another abundant substance that was neither protein nor lipid. He was further able to show that the substance originated exclusively from the nucleus of the cell, so he named it nuclein.


  Miescher did an elemental analysis of nuclein and found that it was comprised of carbon, hydrogen, oxygen, nitrogen, and phosphorus; in effect, these were the same elements found in protein. Nevertheless, the proportions of the elements varied tremendously from protein. Unlike protein, which contained only traces of phosphorus, nuclein contained very large amounts. In contrast, nuclein completely lacked sulfur, which is a significant constituent of protein. Miescher’s conclusion was that nuclein and protein were completely distinct biological molecules, with totally different structures, and presumably unique functions, whatever those functions might be.

  Sadly, Miescher could make no further progress with his studies of nuclein. The tools of a biochemist at that time were only capable of studying small molecules containing but a few dozen atoms, not large molecules with many atoms. Nuclein, as a long-chained polymer, was a giant molecule with millions of atoms. Lacking any techniques to further probe its structure, there would be no further insight into its biological role. Unfortunately, Miescher’s published findings on nuclein joined Mendel’s genetic work with peas among the archives of intriguing but neglected science, waiting for a future generation of scientists to revisit with more powerful analytical tools.

  AN OCTOPUS’S GARDEN

  William (“Willie”) Lawrence Bragg (1890–1971) was a handsome child, with a very kind and considerate disposition. He was the apple of his mother’s eye, and the pride and joy of his father. Although he tended to be shy and humble, his intellectual talents were evident to anyone who shared his company. From his elders, Willie’s genius earned him special attention and access to engaging adult conversation, which further stimulated his young mind. Among his peers, his genius simply made him the target of bullies, and exacerbated the loneliness that plagued his youth.