In surveying the state of the healing arts today, one is surely impressed by the contrasts with earlier centuries. Horrible scourges like smallpox, cholera, and diphtheria which devastated populations even as late as the nineteenth century are now rare or nonexistent in most parts of the world; visualization of previously hidden parts of the body is a commonplace of diagnostic methods; many formerly hopeless infections are readily susceptible to a host of antimicrobial medications; the surgeon's techniques have invaded the cranium, chest cavity, heart, and blood vessels; irreversibly diseased organs are replaced by grafts and transplants of healthy structures or are substituted for by mechanical devices. Furthermore, the inner workings of the cell, the basic unit of the body, have been opened to scrutiny by physical and chemical means. But most of these extraordinary innovations, when viewed historically, are chiefly remarkable extensions and elaborations of past contributions and attitudes.
Among the many changes which stamp the twentieth century, we have chosen some to illustrate this stage of medical knowledge in its development from past to future.
CONCEPTS
Human Genetics
Jean Jacques Rousseau said that when nature finished with him, it broke the mold in which he was cast. But all of us could say the same thing. Mathematicians have calculated that the chances of any two parents producing another one of us exactly as we are, physically, mentally, physiologically, and with the same inborn susceptibilities and resistances are one in several hundred trillion. Yet, research in genetic engineering has progressed so far that it is feasible to challenge the essentially nil possibility of ever having two people exactly alike in terms of their genetic endowment. However, scientists and philosophers are now engaged in considerable debate on whether further research on the transference of genetic substances should not be halted. On one hand, disease and deformity could be defeated before they got started; on the other hand, the possibilities for abuse and accident could lead to havoc and even the destruction of the human species.
The intensive research on inborn or genetic errors started in the 1940s was followed by ever-multiplying investigations that included observing cells in tissue culture. In the 1950s, methods were devised for the accurate study of chromosome numbers and, for the first time, it became clear that the normal human chromosome count is forty-six. Soon, a number of numerical aberrations were discovered, the most common of which is an extra twenty-first chromosome, the cause of Down's syndrome or mongolism. These studies have recently become so refined that individual portions of chromosomes can be identified with various banding techniques which have allowed the accurate description of chromosomal aberrations, leading to more accurate genetic counseling and prevention.
In the late 1960s, techniques were developed for prenatally diagnosing genetic diseases by culturing cells obtained from the amniotic fluid. This has permitted the detection of abnormal fetuses and has expanded the options to include selective abortion of such affected fetuses. Due to these technological advances, the science of human genetics has now become a practical clinical specialty which is capable of proper diagnosis, counseling, and prevention of many serious diseases.
Recent experimental work indicates that at some time it may even be possible to introduce genetic material into defective cells so that they would essentially cure themselves.
Immunology
Immunology began as a rational science in close association with the study of infectious diseases in the latter part of the nineteenth century. Scientists explained why persons who had recovered from certain infections (e.g., smallpox) were often resistant to these same infections during subsequent exposure—an observation long known in antiquity. Even more important, the experimental results led to ways of inducing such resistance before the disease occurred.
In the late nineteenth century, Pasteur, Koch; Behring, Kitasato, Ehrlich, and others placed the principles of immunologic protection on a scientific basis, but successes were not universal. For instance, despite much study and experiment, Koch's attempts to produce a vaccine against tuberculosis failed. Furthermore, a reaction was observed in animals and later in humans which occurred during second or third attempts at immunization. Instead of an increased resistance to the disease or chemical, the inoculated individual had an immediate, severe attack ("anaphylaxis") which often resulted in death by asphyxiation.
At the end of World War II, immunology entered a phase which eventually permitted a molecular biological explanation for many of the immune phenomena associated with infectious diseases and which showed that many other biological activities, not directly related to infectious diseases, actually have an immunological basis. In the 1930s it had been discovered that the factors in blood which carry out the immune activity are in the gamma globulin fraction of the blood serum. Later studies showed these factors to be protein molecules, called immunoglobulins, which are capable of a wide range of interacting functions (e.g., with polio virus, tetanus toxin, diphtheria toxin, ragweed pollen).
Another significant advance has been the recognition that our bodies make a strong immune response against "foreign" material such as the agents which cause infectious diseases. Directly related to this is the recent recognition that the common failure of attempts to graft organs (such as the heart or liver) is due mainly to the biological fact that a recipient's body will react just as strongly against the grafted organ as it would an infecting virus or bacterium. Thus the immune system in general has come to be understood as a mechanism which attempts to distinguish between "self" and "nonself" to protect the former from the latter. Much of contemporary immunological research is directed at understanding the biological mechanisms that regulate this capacity. If the immune system can be specifically and adequately controlled, we might vastly increase the possibility of carrying out successful organ and tissue transplants from one individual to another. In addition, if we learn more about how the immune system deals with cancers, we may be able to understand, and prevent, those instances when the system breaks down and fails to destroy fatal growths.
Virology
For the first thirty years of the twentieth century viruses could be studied only by their pathogenic effects on the animals they infected. They were too small to be seen by the best light microscopes. Then came technical developments such as the invention of the electron microscope in the late 1930s that made it possible to examine the structure of viruses in great detail and to study their relationships and reactions with the cells they infect. Methods were invented for growing cells in culture and for making monolayer cultures which aided exact quantitative studies of viral multiplication and the action of specific antibodies on virus growth. It also permitted accurate observation of the factors involved in the genetics and mutation of viruses.
Advances in biochemistry, biophysics, physical chemistry, and immunology since the 1930s have also contributed greatly to our knowledge of the biology of viruses, and their structure and their relationship to host cells, including their methods of entry, reproduction, and release from them. The practical results of the advances in virology in the twentieth century have had beneficial effects on the health of mankind second only to that of the discovery of antibiotics. Some of these benefits may be cited here. The virus that causes infantile paralysis (poliomyelitis) was first isolated by Landsteiner and Popper in 1909. A noninfectious vaccine for poliomyelitis was devised by Salk and associates and given a nationwide field trial in 1954. In the year before the Salk vaccine was made available commercially (1955) there were 55,000 cases of paralytic poliomyelitis in the United States. Three years later there were fewer than 200. At present, a "live, attenuated" polio vaccine, developed by Albert Sabin, which is taken by mouth and affords long-lasting immunity, has almost entirely replaced the Salk vaccine in the United States.
Another virus disease, German measles (rubella), is rarely accompanied by serious complications and is practically never fatal in children or adults. However, it has been discovered that if a woman contracts rubella while pregnant, her baby might be infected with the rubella virus and might suffer severe and permanent damage or death. A rubella vaccine made with an attenuated tissue-culture-grown strain of virus is now in general use as part of the routine immunization given to infants in the United States, as are vaccines against regular measles (rubeola) and mumps. The measles vaccine has virtually eliminated this serious disease in vaccinated children. Some success has also been achieved in the prevention of influenza, and vaccines are in use which are from seventy-five to ninety percent effective.
Researches on liver diseases conducted during the past twenty years have led to the discovery of two viruses that cause hepatitis (infection of the liver). An experimental clinical trial is being conducted to determine whether antigen from the protein coat of one of these viruses can immunize persons against the virus (hepatitis B virus).
Cancer
Cancer has been known and feared since antiquity, but its incidence could only be speculatively inferred until fairly recently. Indeed, as knowledge of the disease grew in the nineteenth and twentieth centuries, fear increased when people became more aware of cancer without corresponding assurances of an available cure. Even after surgeons were able to extirpate tumors from previously inaccessible body interiors, cancers were still held in terror. Moreover, the overall mortality and rate of survival after treatment were not accurately known until the twentieth century. Statistics reported in this century from all over the world indicate that cancer steadily has been increasing in frequency. For example, the incidence in 1975 was seventy-five percent higher than in 1933, and, furthermore, the organ pattern has been changing. Before 1900, lung cancer was rare; now it is one of the leading causes of death. There are over one-hundred varieties of malignant tumors, but about half of the cancer deaths now are due to growths in the lung, colon, and breast.
Epidemiologists are closely examining the geographic distribution of cancer occurrence for clues to causation. They have discovered that in Japan and Scandinavia stomach cancer is relatively frequent, whereas its incidence in the U.S. is declining and that of pancreatic growths has increased. Carcinomas (cancers) of the colon, breast, and prostate are infrequent in Japan but common in America; yet, Japanese living in the U.S. show a pattern of occurrence resembling that of their neighbors.
Attempts were made as early as the eighteenth century to understand cancer and its causes, but the first major contributions to knowledge came from the microscopic studies of malignant tumors by Muller, Rokitansky, Virchow, and others in the early nineteenth century. Later investigators learned how to transplant tumors, keep malignant cells alive in the laboratory, and induce tumor growth through chemical and biological stimulation. From a great body of experimental and clinical studies, several possible cancer causes have been implicated.
Near the end of the nineteenth century, Julius Cohnheim suggested that cells left over in adulthood from the developing embryo were responsible for later malignant growths, but this could account for only one type of rare tumor, the teratoma. Other scientists of the time considered bacteria, molds, and one-celled organisms to be causative agents, but this concept was short-lived. Later, viruses were shown to cause tumors in animals (notably by Peyton Rous in chickens), but no virus has been proved etiologically related to malignant tumors in humans—even though viruses have been found in association with human malignancies.
Genetic makeup has also been regarded as a causative factor in cancer, and, indeed, some families seem to show a propensity for growths and for certain precancerous conditions followed by a high incidence of cancer. Hormones were thought to have some relation to cancer when it was discovered that removal of the ovaries benefited women with advanced breast cancer and that castration arrested and sometimes caused regression of prostatic cancers. Hundreds of chemicals have produced cancers in laboratory animals, and dozens of environmental and occupational carcinogens (cancer-producing substances) have been implicated in malignant growths in humans. However, it is not known whether these agents directly stimulate cell growth, reactivate dormant viruses, or trigger some intermediate mechanism affecting the cell's biochemical activity.
In the past few decades, the cell has been found to include a multitude of smaller components with definite functions in maintaining the life and activity of the cell itself. Study of these intracellular structures, called "organelles," is bringing us closer to the essential fundamentals of protoplasm and to the ways in which malignant aberrations might begin. There is some evidence of cellular immunity to abnormal, potentially malignant cells, which are perceived as "foreign" and therefore destroyed by white blood cells through both direct engulfment and the elaboration of antibodies. Since a breakdown in this surveillance system seems to permit abnormal cells to multiply and become a malignant growth, attempts have been made through antibacterial vaccines and other protein derivatives to increase the body's general immunity in order to enhance resistance to the growth of cancerous cells. There is also a theory that nutriments, including vitamins and possibly other food elements, detoxify and protect the body cells against carcinogenic agents present in food and the environment.
Quite early in the twentieth century, it was learned that X-ray radiation was hazardous when the discoverer Roentgen himself and other pioneer roentgenologists developed skin malignancies. The effects of exposure to radium salts used to paint fluorescent watch dials were seen in the malignant bone tumors of factory workers who licked their brushes to get a properly shaped point. The association of radiation and cancer was most dramatically highlighted by the increase of leukemias and other malignancies in people exposed to the Hiroshima atom bomb blast. The potential danger of radiation has been so emphasized lately that the safety of even regular diagnostic X-ray procedures has been challenged.
The proof that an abnormal change in an organ is malignant has rested on the microscopic characteristics of a piece of tissue (biopsy) since the nineteenth century. However, other general diagnostic methods developed since then have also increased the chance of detecting cancer: X-rays; visualization of the interior through intubations of orifices; body scanning with radioactive tracer substances and ultrasonic waves; and chemical analyses of the blood. A highly significant contribution to diagnosis was made in 1928 by George Papanicolaou (developer of the Pap test), who reported that he could identify malignant cells among the normal cast-off vaginal cells of women with cancer of the cervix. His observations grew out of studies of animal menstrual cycles, and from then on the technique of exfoliative cytology (the study of cast-off cells) was used to investigate virtually every hollow organ and secreted fluid.
For centuries, virtually the only definitive treatments of cancers were physical and chemical cauterizations, surgical removal of tumors on the surface of the body, and amputation. Surgeons of today are able to remove affected organ systems and even entire regions of the body with relative safety because of advances in physiology, anesthesia, transfusions, and anti-infective agents; however, the mutilations consequent to extensive resections (especially of the voice box, rectum, urinary bladder, limbs, and breast) have stimulated efforts toward rehabilitation, including self-help clubs, clinics, and special training for professionals. Along with observations that X-rays could cause severe damage came the realization that this power could be used to destroy cancerous tissue. As delivery system improvements permitted more effective and less hazardous doses of radiant energy, cures were reported of cancers of the mouth, voice-box, uterus, and, recently, other malignant conditions formerly with very low survival rates.
Another twentieth-century weapon against cancer is chemotherapy. Although arsenic compounds had been used to combat cancer as early as the eighteenth century, nothing new had been added to the armamentarium until it was discovered in World War I and confirmed in World War II that sulphur mustard (mustard gas) and similar chemicals could arrest malignant growths for a short time. Another group of anticancer compounds was added in 1947 when Sidney Farber, following the lead of biochemist Subba Row, found that a derivative of folic acid (an essential nutrient) competed with folic acid and inhibited acute leukemia in children. Michael Heidelberger later synthesized 5-fluorouracil, a chemical agent still much in use today in chemotherapy. Since then a host of chemical agents have been developed from plants and microbes, each acting at different stages in the transformation and growth of malignant cells. Their principal limitations rest on the degree to which they also injure normal cells. The goal of chemotherapy is to find agents with absent, minimal, or controllable toxicity which act selectively on malignant tumors. Slowly and steadily since World War II tumor-growth diseases which were virtually hopeless in the past have become controllable, retarded, or cured by chemotherapy acting alone or in combination with surgery, radiation, immunity stimulation, and other forms of treatment.
The realization that combinations of different chemical agents could halt or cure cancer had significant influences on medical practice, including the emergence of a new specialty, oncology, and an alteration in therapeutic attitudes. Patients formerly given no hope by the medical profession, who in desperation gravitated toward unorthodox "cures" such as krebiozen and laetrile, now attract the full attention of physicians who see the opportunity of improving the chances for survival of patients with advanced malignant growths or at least of enhancing the quality of their remaining lives.
Pathology
The earliest pathologists in contemporary terms were those eighteenth- and nineteenth-century doctors who felt compelled to perform an autopsy ("see for oneself") in an attempt to find physical reasons for the manifestations of disease. Among them, Giovanni Battista Morgagni was the first to arrange and analyze his observations systematically. Rudolf Virchow was the pioneer in fully utilizing microscopic studies in the complete autopsy and set the pattern for the full development of pathology as a distinct specialty.
In the first half of the twentieth century, the techniques and concepts of autopsy pathology soon passed from the realm of general information to that of immediate practicality. It became obvious that samples of tissue, some only a few millimeters wide, could be obtained for microscopic study from a variety of organs, and the interpretations of the pathologist could determine not only the diagnosis and course of therapy, but the ultimate prognosis itself. The techniques for processing tissue for microscopic study were cumbersome and took many days in the early years of the century, but now, if immediate diagnosis is required for urgent therapy, the pathologist is able to prepare tissue samples by freezing and can render a diagnosis within minutes after surgical excision.
Pathologists also began to study the chemicals of the body in their investigations of disease. Small research laboratories were started in many hospital basements, often adjacent to the autopsy room, and it was from these beginnings that the fields of clinical and experimental pathology developed. Disease processes were generated in laboratory animals to provide opportunities for extensive inquiry into the basis, nature, and therapy of similar conditions that occurred in humans.
In the late 1950s pathologists eagerly embraced the electron microscope as a means of expanding their potential for the study of disease. However, it has proved to be useful in the diagnosis of only a small proportion of the diseases that afflict man. Other techniques for the study of subcellular chemistry developed soon after electron microscopy, and both approaches have allowed pathologists to gain new insights into the mechanisms of normal and abnormal cells. In the last decade, many pathologists have sought to define the molecular basis of disease. There is little diagnostic application for these techniques at present, but methods for studying components and products of the cell may prove to be of inestimable value in the care of the patient of the future.
Psychiatry
An account of the development of psychiatry in the present century can begin neatly with the year 1900, when Sigmund Freud published The Interpretation of Dreams and induced a revolution in the field of psychiatry. Earlier, he had studied under Charcot in Paris, who aroused his interest in the problem of hysteria and the uses of hypnosis. In 1895 he had published, with Joseph Breuer, Studies in Hysteria. From these works and the large body of writings which followed, Freud created psychoanalysis. Among its basic concepts are that human behavior is heavily influenced by unconscious mental processes, that childhood experiences play a crucial role in development, and that internal psychological conflict is of central importance in mental life. Early in the development of psychoanalysis, two of Freud's leading collaborators, Carl Jung and Alfred Adler, broke with him and pursued conceptual paths of their own. At a later point, the psychoanalyst Karen Homey also split with the main body of psychoanalysis, as did Harry Stack Sullivan, who wrote extensively on the therapy of schizophrenia.
Another school of psychiatry developed in America during the early decades of the century under the leadership of Adolf Meyer, whose concepts (psychobiology) saw mental illness as the interaction of developmental (i.e., childhood), social, and psychological forces. Nevertheless, psychoanalysis was warmly received, particularly in the United States, and during the 1920s and 1930s a small but active "movement" developed in a number of centers. The impact of psychoanalysis on general psychiatry remained limited, however, until World War II. Prior to the war, psychiatric patients were housed chiefly in large state hospitals which afforded little beyond custodial care. The teaching of psychiatry in medical schools was, by contemporary standards, limited in scope and content, but the war changed all this dramatically. Medical officers on the draft boards, in training camps, and in combat learned at firsthand how prevalent emotional illnesses were and how the theories of psychoanalysis could be adapted to effect therapies for some of the combat neuroses."
The "marriage" of psychoanalysis with general psychiatry as taught and practiced in medical schools and centers after the war gave rise to a brand of treatment called "dynamic" psychiatry, which depends on some form of "psychotherapy" as its chief method of treatment (i.e., an attempt to influence the patient's psychological state by verbal interaction, in which the relationship of the patient to the therapist usually plays a large role).
Two other streams should be recognized in the flow of twentieth-century psychiatry. Some workers see little or no value in the ideas of psychoanalysis or in the "dynamic" concepts derived from it, for they believe that emotional disturbances are caused "organically," i.e., by actual physical changes in the body (especially the brain). Another group feels that social and environmental forces are crucial in the causation of emotional illness and that these forces are not given sufficient weight by either the "dynamicists" or the "organicists." Regardless of theoretical viewpoints, there is considerable overlap in the therapeutic approaches used by psychiatrists who hold the varying viewpoints.
Beginning with the introduction of thorazine in the 1950s, the use of psychologically active drugs has become firmly established. Electro-convulsive therapy, commonly called "shock therapy," has now convinced many of its earlier opponents (who condemned its indiscriminate use) that it has a helpful role in severe depressions and in some acute attacks of schizophrenia. For about ten years during the 1940s and 1950s "psychosurgery" had a vogue, especially lobotomy, which involved cutting certain nerve fibers in the frontal portion of the brain. In the past few years there has been a renewed advocacy of brain surgery (of a more sophisticated kind) as a way of changing behavior, but opposition is strong, involving issues of civil rights and medical ethics.
In 1960, a report by a U.S. commission initiated the era of "community psychiatry," which advances notions that the mentally sick should be hospitalized in their communities, that psychiatric centers should offer a broad range of therapies under one roof, and that psychiatric professionals should go into the field and work with groups within the community.
The past decade or more has also seen the growth of psychotherapies loosely grouped under the heading of "behavior therapy" that aim to modify or eliminate neurotic symptoms by techniques which will condition the patient in such a way as to lead to the desired result. The treatment of patients in small groups of up to eight or ten members has long been recognized as highly useful, but during the 1960s offshoots from group therapy began to appear in the form of "sensitivity training groups," "encounter groups," and "marathon groups" extending through an entire weekend. Psychiatrists have generally condemned these offshoots because of the potential for harm in exposing some people to prolonged, intense emotional stress.
The 1960s and the 1970s have witnessed a virtual explosion of research in psychiatry and in fields relevant to psychiatry, notably in neurophysiology and neurochemistry, which offer small but encouraging glimmerings of the correlation between psychological processes and the physical structure of the brain. Additionally, there has been progress in the genetics of schizophrenia and manic-depressive illnesses.
As psychiatry began the twentieth century it came under the powerful influence of psychoanalysis, an influence which remains strong, though subject to many challenges. Today, the swelling tide of research may remind us that Sigmund Freud, even as he developed his psychological theories, predicted that one day all these processes would be explained in biochemical terms.
Rehabilitation
The concept of "rehabilitation" arose in 1918 out of society's compassion for the mutilated veterans of World War I. Training schools, hospitals, and various institutes were founded on a relatively modest scale, but programs were slow to develop despite laws and efforts by volunteer organizations. It took a second destructive world conflict to prompt governments, notably in the U.S., to develop facilities and programs for rehabilitating the limbless, paralyzed, blind, deaf, and "shell-shocked" war victims. Howard Rusk, as head of the American Air Force Convalescent Training Program, was a strong leader in organizing these programs and in extending them beyond the restoration of disabled persons to the reconditioning of military personnel suffering from any illness or injury.
Now, virtually every medical school and hospital of size has a department devoted to rehabilitation, often as a special concern of the department of physical therapy. For a long time the main focus of these activities was on physical infirmities resulting from amputation, stroke, spinal injury, and limb destruction. In recent decades, rehabilitative techniques also have been applied to disabilities resulting from surgery, such as laryngectomy, colostomy and ileostomy, and breast excision. Self-help groups have sprung up through the efforts of disabled patients themselves and are indispensable aids in restoring people to full, cheerful living. These clubs often are instrumental in educating the healing professions in the proper management of patients and in altering the negative attitudes of the public to the handicapped and maimed.
Public Health
The industrial revolution and the urbanization of nations created both problems and incentives to governmental entrance into the field of public health (a term introduced to government by John Simon, chief medical officer of the Privy Council in London).
In much of Europe, public health measures were mainly centralized, the principal hospitals and schools were state owned, and the delivery of medical care was through a relatively uniform system. By contrast, in America local autonomous bodies of the states and cities were the centers for public health activity, the influential hospitals and teaching institutions were voluntary and philanthropic, and the delivery of medical services was pluralistic and noncompulsory. In eastern Europe, health care delivery organization has been in the category of social service, with health centers at the core and their regulation authoritarian in line with the political and economic system. Since World War II, more and more governments have embarked on public health programs, placing their emphases on those aspects of health and disease which are most in need of improvement in their respective countries.
Coordinated international action on matters of health and disease had been taken from time to time for a specific, limited purpose, such as to contain an epidemic, but broad, organized, cooperative efforts to study and control illness in populations began in 1851 when twelve nations sent representatives to Paris for an International Sanitary Conference. During the next fifty-six years, other conferences led to a more permanent organization in 1907, L'Office International d'Hygiene Publique. Twenty-one countries of North and South America established an International Sanitary Bureau in 1902, later to be called the Pan American Health Organization. In 1948, the Paris-based group, the Health Organization of the League of Nations, and the United Nations Relief and Rehabilitation Administration merged into the World Health Organization (W.H.O.), of which the Pan American Health Organization later became an affiliate. As an agency of the U.N., W.H.O. now exchanges epidemiological and statistical information among its approximately 140 members, publishes technical journals and books, offers advisory services and consultants to countries on request, helps to standardize drugs and techniques, and generally acts as a coordinating body among the countries of the world to maintain the health of the world's population.
As infectious diseases are increasingly brought under control, the health of the aged has begun to enter the focus of public health agencies, with interest centered on the causes, prevention, and management of diseases such as cancer, arteriosclerosis, arthritis, and stroke. Social and occupational influences have also become a concern to those associated with "social medicine," a term introduced by Alfred Grotjahn (1869-1931). Physicians and surgeons have had to adjust to changing roles. As technicians they have had to learn the advancing mechanical techniques of diagnosis and therapy; as healers they have become increasingly involved in managing the psyche as well as the body; as scientists they must face an enormous expansion of physical, chemical, biological, and mathematical information. Now they may have to be sociologists as well, involved in the life styles of their patients, the affected families, and the surrounding population.
DIAGNOSIS AND THERAPY
Radiation
The Victorian age merged into the twentieth century with the outstanding discoveries of X-rays by Roentgen and radium by the Curies. Even in the early years of the century radium proved useful for the treatment of cancer, and the X-ray became a powerful tool for the diagnosis of disease and later for the therapy of tumors. The first obvious use of the X-ray for diagnosis derived from its ability to show broken or deformed bones. Then the shadows began to reveal other abnormalities, in the chest and the gastrointestinal tract, bringing rational diagnosis to the practice of medicine.
In 1897 and 1898, Walter B. Cannon discovered that when he fed bismuth or barium mixtures to geese and other animals these radiopaque suspensions clearly outlined the animals' gullets on an X-ray plate. Today, similar suspensions make the entire alimentary tract accessible to routine radiological examinations.
X-ray facilities in hospitals and even in offices became centers of diagnostic activity. Tuberculosis became detectable early, and cancers were found more readily at stages when they could be surgically removed. Evarts Graham and Warren Cole developed a method of visualizing the gallbladder, and Moses Swick brought the kidneys into X-ray view by employing special iodide compounds. These workers and others thus took the first steps toward visualization of the blood vessels, heart, and other structures by techniques which used X-rays.
While developments in diagnosis proceeded, treatment with X-rays similarly advanced to the stage where high-voltage machines were able to cure some cancers, like those of the larynx and uterus. However, most of the therapeutic uses of X-rays were palliative, shielding the cancerous patient from his pain. Advances in radiation were most marked in World War II. Some of these derived from the availability for both diagnosis and treatment of artificial radioactive isotopes (man-made chemicals emitting radiation) which could be inserted directly into tumors. Fission products from splitting the atom of uranium, and isotopes from bombardment in nuclear reactors, began to replace radium and electronically generated X-rays just after World War II.
Meanwhile, a new concept developed in the early 1970s: diagnosis by computer processing of many beams of irradiation cast into the body from different directions (computerized axial tomography or CAT-SCAN), which provides insight into the interior of the body far exceeding the capabilities of conventional X-ray machines.
A new development from the use of internally deposited radioactive materials arose after World War II. Radioactive chemicals were injected into the body, and their varied distribution determined by a detector of radioactivity ("scanning") has been able to show abnormalities in the lungs, tumors in the brain, growths in bones, and masses in the thyroid, liver, and other organs.
Transfusion
The achievement of safe blood transfusions in humans was a major step in the treatment of hemorrhage and anemia and opened the way for surgical procedures otherwise too dangerous.
Injections into the bloodstream are known to have been performed as early as the seventeenth century. Wine was often instilled into hunting dogs to treat illness, and Johann Daniel Major of Padua gave medications intravenously through thin silver cylinders. He also suggested that blood could be given into the veins, as did others, but there is no clear evidence that he ever did this in humans. Richard Lower in the seventeenth century was probably the first to make an actual transfusion from animal to animal through tubings, and, according to Samuel Pepys, he also administered sheep blood to a young man to try to change his character (results unknown). Nevertheless, Jean-Baptiste Denis is generally credited with the first successful human transfusion. In 1667 he gave three pints of sheep blood to a person with no apparent ill effects, but his subsequent attempt to give calf blood to a dissipated young man—to mollify his fiery nature—led to a severe reaction and death. Although Denis was exonerated in a trial, the Paris faculty forbade future transfusions. Ten years later Parliament declared transfusions to be illegal. The government in Rome also outlawed the transfusion of blood from person to person, but the Royal Society of London maintained its approval.
In the eighteenth and nineteenth centuries, experimental studies on transfusions in animals, and even humans, demonstrated that exsanguinated animals could be restored, that oxygen was transported by the blood, and that blood made incoagulable by whipping out its fibrin content could be administered to animals. Although it finally became clear that the passage of blood from animals to humans was prohibitively dangerous, the hazards of transferring blood from human to human were more slowly realized. Blundell, Ponfick, Landis, Arthur, and Pager reported on some of the physiological and chemical effects of transfusions, but the contributions to immunology by Ehrlich, Bordet, Gengou, and others were the significant openings that led to the clarification by Karl Landsteiner of the existence of blood groups and to the safe incorporation of blood transfusion into medical practice.
In 1901 Landsteiner described the major red blood cell types A, B, O, and later AB. A person with substance (antigen) A in his blood cells had antibodies against B in the liquid part of his blood (plasma), and type B blood cells were associated with plasma containing antibodies against A. The "universal donor," a term first coined by Ottenberg in 1911, had no antigen in the cells but did have antibodies to both A and B in the plasma or serum (plasma without cells or fibrin). Incompatible transfused blood could cause disastrous reactions, including kidney damage and death, but it was not until 1908 that Ottenberg tested the blood of donor and recipient before every transfusion. Despite the virtual absence of previous testing, serious reactions had not occurred more frequently because, with mathematical distribution of blood types, about two-thirds of random transfusions will have no ABO incompatibilities. Even with the precautions of typing and cross-matching, the severe reactions that sometimes did occur anyway were not explicable until other methods of testing and other human red cell types were discovered.
Initially, the transfusionist drew blood from a donor by multiple syringes and injected it into a patient's vein, but by the end of the nineteenth century Alexis Carrel and George Crile were connecting a donor's artery directly to the recipient's venous system. Crile, Ottenberg, Ellsberg, and others later improved on this by developing special needle-cannulas to permit easier vessel-to-vessel connections. Unger eventually devised an apparatus with a four-way stopcock by which blood could be transferred positively from donor to recipient—the first efficient direct transfusions. However, the system was cumbersome and required that the patient and compatible donor be brought together at the same time. This problem was solved by the exceedingly useful discovery that drawn blood could be kept incoagulable by a nontoxic chemical (sodium citrate) and later transfused as needed. Now blood banks containing stored blood are essential parts of every hospital, and techniques have been developed to test blood and to render its components safe for administration.
For many years, blood transfusions and intravenous injections of various solutions were often accompanied by febrile reactions attributed to the inherent nature of the process. Finally, in the 1920s and 1930s, these reactions were proved to result from previously undetected bacteria in the intravenous apparatus and solutions. When rigorous methods were instituted to eliminate such contaminants, febrile reactions caused by bacterial pyrogens disappeared.
Antimicrobials
Paul Ehrlich's search for a "magic bullet" which would seek out and kill germs in the body without destroying host cells was rewarded by the synthesis of arsenical compounds effective in the treatment of syphilis, but the principles he enunciated did not lead to an effective battle against microorganisms until about thirty years later.
Michael Heidelberger's work on pneumococcus (the bacterium that causes lobar pneumonia) enabled investigators to make a specific antiserum for each type of pneumococcal germ, but these sera were of limited effectiveness. Earlier (1917), Heidelberger and W. A. Jacobs had reported that sulfanilamide, an azo dye, destroyed bacteria, but no investigator followed this lead. In Germany, Gerhard Domagk, also testing the antibacterial activity of a variety of dyes, reported that prontosil, a textile dyestuff synthesized in 1908, acted against streptococci in mice. The introduction of this chemical into therapeutics dramatically altered the outlook of many infections, including "blood poisoning," heretofore almost invariably fatal. Trefouel in France showed that prontosil caused the body to produce sulfanilamide, the active antibacterial substance in the dye. Subsequent chemical and clinical studies in the United States and elsewhere yielded a variety of other derivatives: sulfapyridine, sulfathiazole, sulfadiazine, sulfaguanidine, and soluble sulfa drugs for treating urinary infections.
Other antibacterial chemical substances were developed, among which isoniazid proved so effective against the tubercle bacillus that the therapy of tuberculosis was revolutionized. Streptomycin had been introduced earlier, but it required injection and also had potentially serious side effects. Hospitals devoted primarily to the treatment of tuberculosis soon ran out of patients, and the formerly uncertain outlook for the tubercular became dramatically better in the course of a few years.
Pasteur and many after him had observed occasional antagonisms between bacteria. Some investigators tried with varying success in the laboratory and in patients to impede the growth of one species of bacteria by cultures or extracts from another, but the results were either uncertain or the products too toxic. However, a steady stream of publications appearing in the late nineteenth and early twentieth centuries indicated that the higher bacteria, molds, and fungi also destroyed certain bacteria (a process Vuillemin had earlier named antibiosis). Westling in 1912 named one such effective mold Penicillium notatum. Lieske in 1921 and Gratia slightly later proved that a species of penicillium dissolved anthrax bacilli and impeded staphylococci.
In 1929, Alexander Fleming reported in the British Journal of Experimental Pathology his observations on the antibacterial action of penicillium, with the suggestion that the mold culture could be used to inhibit bacteria as a help in obtaining their cultural isolation. Whatever Fleming may have thought of the eventual usefulness of what he called penicillin, there was virtually no further research until Howard Florey and Ernst Chain in England made studies in 1941 which convinced them that penicillin had great therapeutic potential. The only difficulty was that penicillin could not be made in quantity in the laboratory, but this was solved by cooperation between the U.S. government and pharmaceutical manufacturers within two years after Florey and Chain had transferred their work to America.
Other types of antibiotics followed in rapid order. Streptomycin was obtained by Selman Waksman from Streptomyces griseus in 1944 and proved to be useful against a variety of infections, especially tuberculosis. Other strains of the streptomyces yielded additional therapeutic substances such as chloromycetin and aureomycin. Since 1948 many other similar agents have entered the medical armamentarium, each with a special potency but also with its own limitations. As new substances were used their bacterial targets developed resistance, so researchers have had to enter an ever-quickening race to stay ahead of the adaptation by germs to each new drug. Furthermore, antibacterial agents are limited by their inherent toxicity and newly acquired allergies and sensitivities of patients to the antibiotics.
Kidney Dialysis
A bold concept almost entirely a product of the twentieth century is the removal of a diseased organ and the transplantation of a healthy organ from another person. The kidney has been the most successful of the organ transplants, but this would not have been possible without a means of keeping the stricken patient alive while awaiting the availability of a suitable kidney donor.
In 1913, John Abel, L. G. Rowntree, and B. B. Turner arranged a mechanical system, which they called an "artificial kidney," whereby the blood of a dog could be freed of toxic chemicals by circulating it through collodion tubing that allowed toxins to pass out into surrounding liquid while keeping blood substance inside. For this method to be useful to humans, more efficient tubing had to be developed and a more convenient, safe anticoagulant had to be found to prevent the blood from clotting as it flowed through the apparatus. Both requirements were met in cellophane and in heparin, and Willem J. Kolff from The Netherlands then built an effective though cumbersome apparatus in 1945 which was used successfully in humans. Beginning in 1947, modifications by John Merrell, Karl Walter, and many others finally resulted in smaller and more effective machines. Belding Scribner and other investigators so improved the technique of removing and returning the blood through relatively permanent implanted tubings that patients can now be "dialyzed" for an hour or two as frequently as needed (either in a hospital setting or even at home) on a continuing basis or until a compatible kidney donor is found.
Transplantation of Organs
When Christiaan Barnard performed the first heart transplant operation in 1967 at the Groote Schuur Hospital in Capetown, the world realized that a new era of surgery had arrived. Up until that time the public had been minimally aware of the advances of kidney transplantation and transplantation research. But when a heart was transplanted the public's emotions ran wild, and newspapers throughout the world proclaimed in headlines daily advances in the transplant world.
The first bonafide report in the medical literature of organ transplantation came from Vienna at the turn of the twentieth century when Emerich Ullmann transplanted a dog's kidney from its normal position to the neck. This autotransplant (from the same individual) worked quite well, but when Ullmann transplanted a kidney from one dog to another dog its function was short-lived. Later, he successfully transplanted a dog's kidney to the neck of a goat, the first xenografting in scientific annals.
Ullmann's work was taken up by Alexis Carrel, who in 1912 was the first researcher in America to win a Nobel prize in medicine or physiology. Carrel realized that a major technical difficulty was the lack of a method of rapidly reestablishing a normal blood circulation to a transplanted organ, and he devised successful surgical techniques for suturing small vessels. Working with Charles Guthrie, he successfully performed a dog kidney autotransplant in 1905, but the recipient eventually died when the kidney failed.
Research in transplantation lay dormant until 1923 when Carlos Williamson concluded that underlying the failures was a fundamental biological principle which had not yet been identified. Examining rejected tissue under a microscope, he described the characteristics of the rejection phenomenon for the first time. In the 1950s, Emile Holman came to the conclusion that rejection of grafts was due to a special antibody for that tissue, that if a host received skin grafts from three different donors each would be rejected by a different antibody formed expressly in response to the genetic makeup of that particular donor. At about the same time, MacFarlane Burnet in Australia and Peter Medawar in England, working separately, achieved a significant breakthrough by discovering the means by which a newborn animal could be permanently induced to tolerate a foreign protein, for which they received a Nobel prize in 1960. However, a number of attempts to transplant kidneys continued to fail because there was still no way to effect tolerance in adult humans to a donor organ. Then, in 1954, a team at The Peter Bent Brigham Hospital in Boston transplanted successfully and permanently a kidney from an identical twin to his brother who was dying of kidney failure. But the transferring of a kidney in nonrelated persons was not successful until researchers were able to prevent the rejection of transplants through drugs that lower the recipient's immunological responses. Thereafter kidney transplantation became feasible on a reasonably large scale.