Heredity under the Microscope

Chromosomes and the Study of the Human Genome

Soraya de Chadarevian

• Publisher: University of Chicago Press
• Year: 2020
• ISBN:
  9780226685250
• Topic: Biological Sciences
• Subtopic: Science General
• Index: Biological Sciences

By focusing on chromosomes, Heredity under the Microscope offers a new history of postwar human genetics. Today chromosomes are understood as macromolecular assemblies and are analyzed with a variety of molecular techniques. Yet for much of the twentieth century, researchers studied chromosomes by looking through a microscope. Unlike any other technique, chromosome analysis offered a direct glimpse of the complete human genome, opening up seemingly endless possibilities for observation and intervention. Critics, however, countered that visual evidence was not enough and pointed to the need to understand the molecular mechanisms.
 
Telling this history in full for the first time, Soraya de Chadarevian argues that the often bewildering variety of observations made under the microscope were central to the study of human genetics. Making space for microscope-based practices alongside molecular approaches, de Chadarevian analyzes the close connections between genetics and an array of scientific, medical, ethical, legal, and policy concerns in the atomic age. By exploring the visual evidence provided by chromosome research in the context of postwar biology and medicine, Heredity under the Microscope sheds new light on the cultural history of the human genome.

Chapter One

Radiation and Mutation

The history of human chromosome research has often been told as a history of sometimes fortuitous, other times hard-won technical improvements in the art of preparing and analyzing chromosomes. In the early 1950s, cell-culturing techniques and the pretreatment of tissue with hypotonic medium that swelled the cells and spread apart the chromosomes did away with the need to work from serial sections in which the chromosomes were clumped together and sliced up. The improved preparation techniques inspired new work with human chromosomes. Together with the use of colchicine and the development of squash techniques, the number of human chromosomes was revised and modern cytogenetics began. The introduction a decade later of staining techniques that made it possible to distinguish every single chromosome by its characteristic banding pattern made everything that had come before appear “paleolithic,” and cytogenetics came into its own until molecular technologies and new fluorescent marking techniques once more dramatically increased the resolution of chromosomal observation.1

Yet this story, as close as it brings us to the laboratory bench, begs the following questions: What attracted researchers to the study of human chromosomes, and what sustained their interest? What gave importance to the observations they made?

Postwar genetics was deeply intertwined with the challenges and opportunities of the atomic age. This holds true specifically for human chromosome research. If we search for the atomic connections, they are pervasive and deeply mark the history of the field. Efforts to establish the effects of radiation in humans, along with renewed interest in the role of chromosome mutations in causing cancer—a disease often linked to radiation exposure—provided new incentives to develop methods to study human chromosomes at a time when various countries were developing atomic energy for military and civilian uses. Many of the decisive preparation techniques for human chromosome analysis (or karyotyping) were originally devised to study the chromosomes of humans or experimental animals with radiation-induced leukemia, a cancer of the white blood cells also dubbed the “pestilence of the atomic age.”2 This was true for both the bone marrow method developed by Charles Ford and Patricia Jacobs at the Radiobiological Research Unit at Harwell, Britain’s Atomic Energy Research Establishment, in the mid-1950s, as well as for the peripheral blood method developed by Peter Nowell and David Hungerford in Philadelphia that soon replaced it.

Similarly, the researchers involved in developing and promoting human chromosome analysis in the middle decades of the twentieth century were deeply involved in things nuclear. They worked in institutions or projects funded to assess the effects of radiation. They visited atomic bomb explosion sites in Japan to study the survivors and test sites in the Pacific to record and plan experiments. They sat on numerous national and international committees dealing with the effects of radiation on humans, wrote reports to their respective governments, suggested “permissible doses” of radiation based on what they knew was incomplete knowledge, and forcefully argued for the urgent need to expand genetic research to increase knowledge on the genetic structure of human populations and so help assess the effects of radiation.3 The topics they tackled included the effects of radiation treatment in the clinic, studies of atomic bomb survivors, and the long-term effects of low-dose radiation exposure on the workplace or from fallout. Funds were forthcoming, and policy makers, the media, and the public eagerly received the results.

This chapter substantiates the claim that concerns of the atomic age provided tools, urgency, and visibility to human chromosome research. It traces the intimate connection of chromosome research with efforts to capture the effects of atomic radiation in humans in the aftermath of the atomic bombings in Japan and in the face of the continuing development of atomic energy for military and civilian uses. It follows the careers of key postwar protagonists of human chromosome research and reflects on the sites and resources of their work. The chapter then takes a closer look at two lines of research that defined cytogenetic research agendas while directly responding to atomic age concerns: the chromosomal study of various forms of leukemia and the use of chromosomes as a tool to measure exposure to radiation and other workplace and environmental pollutants. At the basis of both these endeavors was the aim to visualize mutations and to study and monitor their effects. The term atomic age is here used to denote the first decades following World War II—a time when nuclear politics was dominating many aspects of public life, from military strategies to foreign policy and the economy, from national research agendas to public debates.4

Visualizing Mutations

The mutational effect of radiation literally exploded as an issue with the dropping of the two atomic bombs on the populated cities of Hiroshima and Nagasaki that marked the end of World War II. As historians have argued, the atomic bomb was conceived as a super-explosive rather than an atomic weapon in the more literal sense.5 People exposed to the effects of the bomb were expected to die, not to survive the explosion and continue to suffer from the lingering effects of radiation.6 The first images that reached the public showed the material devastation produced by the bomb but did not reflect the plight of the survivors. The harrowing pictures of the “walking dead” taken by photojournalist Yoshito Matsushige on the day the bomb fell on Hiroshima, for instance, were published only after the end of the American occupation.7 Nonetheless, the radiation effects of the two bombs on the surviving population quickly became a medical, diplomatic, political, and ethical problem of vast dimensions that was further complicated by the postwar development and testing of atomic weapons and rising Cold War tensions.8

Susan Lindee has described how the genetic effects of the bomb moved to center stage in the work of the Atomic Bomb Casualty Commission. Apparently, this was largely because of the interest of the leading scientist on the American team, James Neel. The commission based its first assessment of the genetic effects of the atomic bombings on such indicators as the rates of stillbirths, sex ratio, congenital anomalies, infant mortality, bodily dimensions, and life span in the children of the survivors. All these factors were considered related to the mutational effects of radiation. Lindee has discussed the problems with these indicators and the way the choice reflected political and social concerns. Mutation, she argued, was defined as a “dangerous, threatening, or socially disturbing trait with implications for future human survival.”9 The studies based on these parameters were declared “inconclusive.”10 Scientists used the results to argue for further investigations into the genetic effects of radiation.11 The survivors of the atomic bombings in Japan would remain a test population for a long series of new studies and approaches. Meanwhile, the publication of reassuring reports on the health of Japanese children served to pacify alarm over the deleterious effects of atomic radiation in the population who had suffered an atomic attack and also people back home who were contending with reports of atomic fallout from weapons testing.

Also a concern from the beginning and intensively studied were the somatic, cancer-inducing effects of the bomb. Little was known about the actual mechanisms by which radiation acted on organisms, but somatic effects (showing up during the lifetime of people exposed to radiation) and genetic effects (due to mutations in the reproductive cells and showing up in the next generation) were treated as separate effects.12 This separation would eventually break down—not least because both effects could be studied at the level of chromosomes—contributing to a vastly expanded understanding of the genetic, including reproductive and somatic, effects of radiation and its connected risks.

Meanwhile, the decision by the American, British, French, and Russian governments to pursue the development of atomic energy for military and civilian uses was accompanied by vast new programs for radiobiological research. Radiobiological research centers were established in close proximity to nuclear energy research and development sites such as the Atomic Energy Research Establishment at Harwell in the United Kingdom and Oak Ridge National Laboratory in Tennessee, the uranium enrichment site of the Manhattan Project that later moved to civilian control.13 At Harwell, the brief of the Radiobiological Research Unit, established in 1947 and funded by the Medical Research Council (MRC), was “to investigate the toxic actions of radioactive substances and to develop methods of protecting workers against them.” This was before the fallout debate raised concerns about the effects of radiation not just on the workers handling radioactive materials but also on the population at large.14

For the MRC, the foremost government funding body for fundamental medical research in the United Kingdom, this was part of a broader commitment to harness the advancements of nuclear physics for biology and medicine and to advise the government on safety issues regarding the new field of nuclear radiation. This double commitment in many ways reached back to the role of the council in overseeing the development of radium therapy in the interwar years. It was substantially strengthened by the general advisory functions with respect to medical research matters the MRC assumed during World War II.15 The MRC was directly responsible to Parliament (rather than to one of the ministries), and therefore regarded itself as independent from political pressures. It became responsible for much radiobiological work after 1945. As often noted, the situation was different in the United States, where the Atomic Energy Commission both promoted nuclear energy and funded much of the research assessing its health risk—a dual role for which it was often vehemently criticized.16

An important program, pursued both at Harwell and at Oak Ridge, was the long-term low-dose irradiation of vast populations of mice to establish safe limits for human radiation exposure.17 Both centers profited from the on-site availability of nuclear reactors for their experiments. To establish mutation rates, researchers set up classic crossing experiments using the multiple recessive method, also known as single locus test. The first step involved developing a stock of mice that was homozygous for several recessive mutations that could be easily identified, thus allowing for quick scanning. Seven mutations were chosen, including characteristics such as brown coat, short ears, and pink eyes. In the experiments, sperm from irradiated wild-type male mice was used to fertilize females carrying two doses of a recessive mutant gene. If irradiation had produced mutation in the male, the offspring would show the mutation. If no mutation occurred, the offspring would look like wild type.

Despite large investments in the question of the long-term effects of low-dose radiation, the answer remained elusive. Irradiation experiments at Harwell and Oak Ridge—using millions of mice and other organisms as well as increasingly sophisticated irradiation regimes—continued well into the 1990s. Yet concerns about the genetic effects of radiation also stimulated parallel efforts to visualize mutations on the chromosomal level.18 At Harwell, this aim was pursued in the Cytogenetics Section under Charles Ford. Ford became one of the key players in the establishment of human chromosome research in the 1950s, in the United Kingdom and internationally. His career, much like that of other chromosome researchers at the time, illustrates very well the changed opportunities for studying human chromosomes in the atomic age. The next section introduces Ford and some of the other protagonists of the following chapters, pointing to the multiple connections of their work to concerns surrounding radiation. Their career paths also demonstrate the close interactions between the select group of human chromosome researchers in the 1950s and early 1960s. The geographic proximity of various centers in the United Kingdom facilitated exchanges and this may well have contributed to the initial British dominance of the field.19 Yet attention is also drawn to the participants from other countries who attended the first human chromosome standardization meeting in Denver in 1960. Participation at the conference was restricted to researchers who had already published a human karyotype showing forty-six chromosomes. This was a small club of thirteen people. Nuclear issues were never far from their endeavors.

Atomic Careers

A trained botanist, Ford moved to the newly established Radiobiological Research Unit at Harwell in 1949, after having spent three years at the Department of Atomic Energy at Chalk River in Canada, where he had studied the biological hazards of radiation using the root tips of the broad bean Vicia faba.20 Once at Harwell, Ford and his collaborators set out to develop the technologies to study radiation-damaged chromosomes in mammalian cells—not without initial reluctance to put the elegant plant chromosome work aside. Plant root tips, with their rapidly dividing cells, were a convenient model system for radiation research, yet there was an urgent need to study the effects of radiation on chromosomes of mammalian organisms such as mice, rats, and rabbits, which could be more easily extrapolated to humans. Several technical advances in mammalian chromosome preparation techniques at the time were imported from botany. These included cell culture methods, as well as the use of colchicine, hypotonic medium, and squash techniques, all of which served to move away from working with embedded and sectioned tissue samples. Ford’s...

Table of contents

• Cover
• Title Page
• Copyright Page
• Contents
• Introduction
• 1.  Radiation and Mutation
• 2.  Chromosomes and the Clinic
• 3.  X and Y
• 4.  Scaling Up
• 5.  Of Chromosomes and DNA
• Epilogue
• Acknowledgments
• Note on Sources
• Notes
• Bibliography
• Index