The lucky ones were vaporized: Hiroshima, Nagasaki, and genetics

I was alive when the two bombs, Little Boy and Fat Man, were dropped on Japan, but I was too young to know about it.  Only years later did I know in some abstract sense what dropping the "A- bomb" was all about.  It was a merciful act, designed to end WWII before hundreds of thousands of soldiers on both sides were slaughtered or disarmed (literally), no?

Bombs away.  Little Boy (wikipedia)

I'm reading a new book Hiroshima Nagasaki, by Paul Ham.  According to the author, by the time our testing was over and we were ready to deliver our babies, both the Allies and the Japanese knew that Japan was finished.  The Nazis had just surrendered, having suffered but a fraction of what they deserved, and the Allies' attention could be turned full-bore on Japan.  Pincers from China, Russia, the US and Britain were closing in on the besieged island Japanese.  But if those suicidal maniacs (as we were told they were) decided to fight to the last samurai, countless good guys, as well as suicidal maniacs, would suffer.  If we let the Japanese have a look at what we could do, then they'd surrender quickly and no battle for invasion would be needed.

To make sure they got the message, the Allies decided to give them a very close look, not at a bomb dropped in the harbor but  the first directly on Hiroshima, not off-shore. The second was insurance. There were about 100,000 killed outright and 100,000 injured.  There were hundreds of thousands who survived exposure to one (or in a few cases both) of the bombs, and of those who did not die of radiation sickness, life would never be the same. While some managed to have basically normal, or even happy lives, for many or most there was a huge lifelong trauma of radiation-related diseases, disfigurement, social ostracization, suicide, and other forms of misery.  PTSD hadn't even been defined, but in some ways, the lucky ones were vaporized.

MT readers may not know some of the biomedical aftermath and the way that these events not only ended a war but began a search for understanding of the biological effects of radiation exposure on humans.  At war's end, the Atomic Bomb Casualty Commission (later renamed the Radiation Effects Rsearch Foundation, or RERF) was established to do research on the surviving victims.  The victims' location when the bombs fell, shielding (e.g., in a house, out in the open), and resulting dose exposure were estimated for tens of thousands of bomb survivors.  Their health was followed by RERF staff with regular examinations and so has been the health of their children in the nearly 70 years since the events.

Two leaders of the studies of these effects were the late Jim Neel and still-kicking Jack Schull.  They were leading geneticists at the time (indeed, were among the founders of the American Society of Human Genetics).  I was fortunate to be Jim's post-doc at Michigan and to have Jack on my PhD committee and then as my department director in Houston for 13 years.  I was not directly involved in the RERF, but I did co-author with Jack a book-length report on radiation and cancer for a UN radiation agency.  So while I've never been to Japan, I've followed some of what has gone on there, from a genetic point of view, for many years.

Why genetics?
Why would geneticists get involved in studies of A-bomb survivors?  Wouldn't trauma surgeons, plastic surgeons and the like be the ones to be involved in the post-bomb medical studies?  The answer takes us deep in to the nature of genetics and evolutionary theory of the time.

Before the war, it had been shown experimentally that atomic radiation was mutagenic.  Whatever genes were, radiation could induce heritable changes in them.  Ionizing nuclear radiation was one source, but we were exposed to others, such as cosmic rays, chemicals and who knew what else.  If mutations caused disease or deformity, then a species had to have a way to purge them from its population if it were not to be mutated into extinction.  Some theory held that natural selection worked to preserve favorable genetic variants by making them dominant and hence to protect the diploid organism from new mutations, which were held mainly to be harmful.  But if most new mutations were thus recessive, if they subsequently rose in frequency eventually matings would generate recessive homozygotes, and hence severely defective, offspring.  Humans had adapted to the 'load' of mutations from these normal exposures, but could we sustain to a huge additional dose imposed by modern life?  The survivors of Hiroshima and Nagasaki provided a kind of gruesome natural experiment to answer this question.

At the time it seemed that there was plenty to fear.  The A-bombs were a lesson, but after the war, we were experiencing plenty of routine exposures:  we had nuclear testing and the fear of the damage of fallout that from above-ground tests was wind-borne to much of the whole globe.  There were growing diagnostic and therapeutic exposures to radiation.  There were casual uses such as in shoe stores to see how things fit your feet (and kids like me played with them while our parents shopped for shoes).  We were getting annual chest x-rays to look for tuberculosis, and dentists were firing away (I once had a job evaluating the quality of calibration of dentists' x-ray machines--which was highly variable). Radiation, though itself a carcinogen, is even a treatment for cancers that had arisen for other reasons.  Nuclear power stations had employees and the uranium that fueled them had to be mined, processed, and shipped.  How much radiation could workers safely be exposed to?

So, questions about the nature of exposure were cogent at the time.  Indeed, Neel's studies of the Yanomami and other Amazonian tribes, on the results of which I did some work early in my career, were in part designed to see what the genetic load was like in indigenous populations today, who like our species' ancestors were not exposed to these industrial-world dangers, to compare with what we were finding in ourselves--including by the RERF.

In the first decades after the attacks studies of inherited mutation were first done using various indirect indicator traits like still or defective births as indicators; later a few protein polymorphisms were found whose variation could be detected by electrophoresis during the decades after the attacks. These various tests for gonadal mutation were done on the births of those pregnant when exposed or the children of exposed survivors who because they hadn't been so disfigured or shunned that they were able to marry. Basically no excess mutations were found in these children, nor did they suffer any unusual or early diseases or shorter lives that might suggest heritable effects of radiation. Essentially, very little if any excess mutation was found in these studies.

In a sense, this result was presented as 'no mutations were found', a surprise given the expectations at the time, based on the known mutagenic role of radiation.   However, what was instead clearly found rather quickly was that survivors were at greatly increased risk for cancer.  First to appear clearly were leukemias, excess of which showed up in the first decade or so. Then excess cases of some solid tumors arose, with somewhat less risk and after longer latency times, and this excess continued throughout the survivors' lives.  There were and still are major debates about the dose-response relationships, but the carcinogenic effect of exposure in survivors was very clear.

The techniques for germ-line mutation detection were crude by today's standards, but I think the result (no real excess of mutations) still generally holds.  After all, gonadal tissue is a small target in terms of numbers of at-risk cells, relative to lungs and other organs.  And harmed gametes might just not have a chance to compete for fertilization and gestation, and never show up as a viable mutated baby who could carry the change into future generations.

But the cancer findings showed clear evidence of radiation as a mutagen, which makes sense given that cancers are to a fundamental extent diseases of changes that transform individual body cells so they no longer behave as they should for their particular organ context. They divide and spread.  So cancer is a genetic disease, and radiation is a mutagen, and that's why it's also a carcinogen.

Findings like these for cancer fit into a genetics research perspective, and with huge improvements in sequencing and genotyping technologies we gradually have grown to view genes as the major elements of biological causation.  Even in the Japanese survivors, however, an important fact is that except for leukemias, solid tumors didn't arise for many years, usually decades, after the bombings. This must reflect the fact that it takes many genetic changes to turn cells normal enough to enable gestation and postnatal life into tumor cells.  The victims who experienced post-exposure cancers may have inherited some risk variants, but the latency time implies that they had to await some for number of additional, non-radiation-related mutations to occur and supplement those caused by the exposure, before a tumor arose.

Relevance to today's genetics
These things are relevant to the insistence today that genes are responsible for major diseases.  For decades, starting with Archibald Garrod's pioneering use of Mendel's ideas to show that some metabolic diseases clustered among close relatives ('segregated') in the way Mendel's selectively chosen pea traits did, human genetics was about clear-cut, basically single-gene pediatric traits. Indeed, Neel related in his autobiography (Physician to the Gene Pool) that as a medical student he had been discouraged from doing genetics as a research clinician because there was nothing beyond rare, uncureable pediatric traits to study.  Fortunately, he ignored that advice.

A 1954 book by Neel and Schull pioneered the idea that genetic factors might be contributing to late-onset traits like cancer (not associated with radiation) and other diseases that aggregated but didn't segregate in families, that is, genes with weak effects (because if they had strong effects they would segregate, a point still not well-learned by today's army of geneticists).  This foreshadowed the era of genetic epidemiology that has gradually led to the notion that your inherited genome is like your palm-lines in foretelling your life and fortunes.  That genetic variation could 'cause' traits that take decades to develop was a strange thought, and we should recognize why we have such trouble finding major factors for such complex, non-segregating late-onset diseases.  The A-bomb studies clearly showed that somatic mutation was a result of the exposure of survivors.  That is one reason I've personally been interested in somatic mutation and its sources and consequences, and why I am skeptical about what I think are highly exaggerated notions about specific genetic causation of complex traits.

A commenter on the first published version of this post noted, correctly, that Jack's 1990 book Song Among the Ruins gives another treatment of postwar Japan, including much more about the biomedical studies and experiences, and the mutational findings.  Plus, it's very movingly written.

I can't judge Ham's book and its political or historical inferences.  He asserts that the bombs were dropped perhaps needlessly for reasons of global politics involving competition among the winners for domination of Asia.  Dropping the bomb let us get there first.  However, for me, the book presents a disturbing, sad chronicle of what the survivors' experienced, though it is mainly about the geopolitical history.  It is easy for us to have great sympathy for the horrified, scarred, often socially shunned survivors of events that the rest of the Japanese population would rather forget or pretend never happened.  It is easy to criticize the political motivations made at the time, when fallible mortal leaders had to make judgment calls in a very complex political web with countless military and civilian people being horrified, mangled, or killed on a daily basis.  Other nations on both sides were known to be working on a nuclear bomb.  And the Japanese were not innocent babes, and had committed unconscionable cruelty and horror on their enemies.

Of course, as always the ordinary citizen was caught up in global affairs beyond his or her control--as we are today.  The lesson isn't to blame countries for their wartime atrocities, because no country is angelic under such stress.  The lesson is to prevent such conflict in the first place.  That seems to be a lesson nobody can learn, given what we see today, even in Europe and Asia, even among the WWII belligerent countries, always pressing, edging toward conflict.  We are prisoners of our emotions and our short memories.

But geopolitics and the shackles of history aside,  it is interesting to think about the ways that radiation mutagenesis and carcinogenesis have molded our thoughts more broadly, when it comes to the causes of death and disease even in ordinary times like ours.


[this has been edited from the original posting, to correct grammatical and phrasing mistakes]

Japan's tragedy: the genetics of radiation exposure

The Japanese are undergoing severe trauma in many ways and, cruelly, Nature may have delivered some blows below the belt.  Despite being the acknowledged best in the world at designing and building nuclear power plants, Nature's wrath exceeded anything they could have anticipated.  The earthquake and tsunami were the beginning of a terrible 'perfect storm' of events.

The detonations of atomic bombs over Hiroshima and Nagasaki, now nearly 70 years ago, had a curious impact on both the survivors and the rest of the world.  At the time, radiation was a known mutagen, and everyone was concerned about the mutagenic effects of fallout, therapeutic radiation, and industrial exposures (as in uranium miners).  The fear was that humans exposed to radiation would suffer mutations but since, according to evolutionary theory of the time, many of them would be recessive, they would be transmitted from generation to generation.  In our huge societies, two carriers of the same mutation would be very unlikely to mate.  But if we continued to accumulate harmful mutations, eventually there could be a very big genetic burden on society, as a frightening fraction of fetuses could be affected.

Well, that turned out not to be much of concern, for many reasons.  Most directly, there was no elevated frequency of protein-coding mutations detected in studies of offspring of survivors of the bombs in Japan.  This was compared to people who were unexposed in Japan, to different dose levels, and even to the Yanomami Indians of the Amazon basin (a main reason the South American studies were funded at the time).

Unfortunately, radiation didn't get a clean bill of health. Instead, about 5 years after the bombings, increased levels of leukemia were found in the Japanese survivors.   And if all cancers are considered, the increase persisted for decades--essentially a life-long excess risk.   This is the long tail of ionizing radiation damage.

Hopefully, the wind will carry the radiation released this week in Japan out to sea, where it will disperse and be of no concern.  If it does hover over a city, those who do not experience very serious exposure will have to be followed, perhaps for the rest of their lives, in an attempt at early detection of radiation-induced tumors.  To do this effectively, estimates of each individual's exposure will undoubtedly be attempted--based on where they were when, indoors or outdoors, and so on.

Radiation is a mutagen, but the type of risk depends on the type of exposure.  WWII exposure in Japan was mainly a quick burst of gamma radiation passing through the body, and causing mutation in cells along its path.  In the current case most of the dosage will be inhaled or on the skin.  It could persist (e.g., inhaled isotopes could lodge in mucous membranes as they decayed over the years).  Much of the externally deposited radiation probably won't pierce the skin, but isotopes breathed in or ingested could be a problem for exposed organ parts (like lining of the lungs).  That could make detection somewhat easier as fewer tissues may be at risk, though it doesn't make the resulting disease less serious.  But all of these mutations are in somatic, not germline tissues.  So although this isn't of much comfort now, this probably means, again, little damage to the gametes and hence little introduction of new mutation into the Japanese gene pool.

We hope this is just a bit of speculation, and that successful control and friendly winds will blow this problem away, and leave the people of Japan safe--at least from radiation-induced disease. They already have plenty of problems to deal with.

Scat CAT! Get the picture?

A story on the Dec 15th NPR site (Radiation From CT Scans May Raise Cancer Risk) provides a discussion of the risks of cancer induced by the proliferating use of CT scans in medicine. The estimate is that as many as 29,000 future cancers may be caused by the 72 million CT scans done in 2007 alone, and as many new cases induced each coming year if practices don't change. The story also presents a graph of these possible cases (and about 15,000 of them estimated to be fatal).

It's sometimes said, reassuringly, that the amount of radiation a patient receives from one chest scan is equivalent to the natural radiation exposure from one transcontinental flight, but the amount of radiation can vary so much per scan that some are equivalent to 500 transcontinental flights. Or even the dose received by survivors of the atomic bombs dropped on Hiroshima or Nagasaki. And those caused, and are still causing, increases in cancer rates in those survivors (more or less so, depending on distance from the epicenter). This is no joke, if you get the picture.

We've said many things before about competing risks, and this is an excellent example. It is directly comparable to the recent controversies about mammography, though (as we've discussed in previous posts) the recent controversy has been about over-detection of tumors that would regress on their own, rather than about the risk of x-ray induced cancer, but that was a major reason why the recommendation has been not to start until menopausal or post-menopausal years.

A major part of our book is devoted to describing how life is characterized by partially sequestered environments -- in this case, cells -- that respond to each other and behave as a result of signaling and related processes. Radiation damages DNA and can cause a gene to be mutated and or misexpressed, altering the cell's function. Our cells have DNA-repair mechanisms that can detect changes under some conditions (e.g., when the two strands no longer match and fit closely together because one of the corresponding nucleotides has been altered).

But if the cell doesn't detect and repair the change, the cell permanently is on a misbehavior track. This can be especially dangerous when the mutation is in the genes responsible for DNA repair itself.

Since a tumor cell, unlike a bacterial cell, is part of you, your immune system may not be able to tell that it's not doing its proper job. It or other tissue-order-retaining mechanisms may thus fail to maintain the proper order. The tumor cell divides, and divides, and divides: it is an internal engine of life that is no longer receptive to external signals, and the external police can't detect it.

But the whole picture is more than a CT inset. If CT is useful, it's presumably because it detects serious disorders. We know now that a fraction of those would not actually need to be treated, as in the case of mammography and other diagnostic tests. That means needless cost and morbidity. On the other hand, if the CT scans do lead to effective treatment of serious disease, then people will live longer. This means that some of them will get cancer (unrelated to the CT radiation exposure) or other diseases of aging, as well as the iatrogenic (doctor-induced) cancers. So there's no simple winning or losing here.