When epidemiologists look at the rise and fall of diseases in a global setting over long periods of time, they provide a perspective quite differ- ent from that available to patients and practicing physicians. Such a per- spective suggests a cautious response to the hyperbole surrounding the latest ‘‘medical miracles.’’ The analysis of speciﬁc examples and general trends in mortality and morbidity have led some historians, epidemiol- ogists, demographers, and critics of medicine to question the role of medicine throughout history and, therefore, the probable effect of mod- ern medical technologies on mortality and morbidity in the foreseeable future. Indeed, in looking closely at the leading causes of death in the United States today, health policy advisors generally suggest that the most important focus of attention is no longer the conquest of disease, but the containment of medical costs.
At the beginning of the twenty-ﬁrst century, the leading causes of death in America were heart disease, can- cer, stroke, diabetes, accidents, and Alzheimer’s disease. Instead of dying of childhood diseases, or an emergency appendectomy, Americans are more likely to spend decades in a nursing home with Alzheimer’s disease or enter an unhappy middle age sprawl and die of liposuction. Whether longer lives represent an increase in quality as well as quantity is open to question, but suicide (which is likely to be underestimated) was number 11 in the listing of the causes of death in the United States.
The United States devotes more of its economy to healthcare than other industrial countries. Americans spent about 14 percent of gross domestic product on healthcare, while other advanced nations spent about 10 percent. In 2000, healthcare accounted for 10.7 percent of the gross domestic product in Switzerland, 10.6 percent in Germany, 9.5 percent in France, and 9.1 percent in Canada. Medicare spending, for the elderly and disabled, rose 7.8 percent in 2001, while spending under Medicaid, the federal-state program for low-income people, increased by 10.8 percent. Prescription drugs were the fastest-growing category of healthcare spending. In 2001, spending on drugs exceeded spending on nursing homes and home healthcare combined. Pharma- ceutical companies say prescription drugs consumed only about ten per- cent of total healthcare spending in 2001. Spending for hospitals and doctors accounted for more than 50 percent.
As measured by life span and infant mortality, however, most developed nations are healthier than the United States. Moreover, Americans do not have more medical services than residents of other nations. In 2001, the United States had 2.7 doctors per thousand people, compared with a median of 3.1 in the countries in the Organization for Economic Cooperation and Development (OECD). The United States has 2.9 hospital beds per thousand people, compared with the OECD median of 3.9. Germany has 6.3. Researchers concluded that Americans are charged more for doctors, hospitals, drugs, and, especially, for administrative expenses.
Although healthcare spending and access to medical care are hotly contested issues, some studies seem to suggest that increased spending on healthcare does not necessarily lead to signiﬁcant and measurable improvements in health. In contrast to most goods and services, the sup- ply of healthcare (as measured by the numbers of physicians, specialists, diagnostic and therapeutic equipment, and hospitals) seems to drive demand. Many complex economic, political, and cultural factors are involved in patterns of distribution and usage of healthcare resources, but analysts point to major discrepancies in spending that are not reﬂected in vital statistics. For example, despite major differences between Medicare spending for senior citizens in Miami and Minneapolis, life expectancy was essentially the same. Studies that analyzed the relation- ship between the availability of neonatal intensive-care facilities and specialists and infant mortality rates reached a similar conclusion. That is, increasing the availability and usage of healthcare resources increases costs, but does not necessarily result in obvious or measurable improve- ments in health and longevity.
Nevertheless, the cost of healthcare and the number of Americans without medical insurance are expected to increase rapidly. Some health policy experts argue that debates about how states and individuals should pay for medical care should be informed by a healthy skepticism about the cost-effectiveness of medical treatments and an understanding that newer, more aggressive, more expensive care does not guarantee better care, better health, or longer life expectancy. For example, studies of the mechanism of heart attacks suggested that increasingly popular aggressive treatments, like bypass surgery, angioplasty, and the insertion of stents (wire cages that hold plaque against an artery wall in order to maintain blood ﬂow) might be useless, as well as dangerous. Preventive measures, such as giving up smoking, lowering cholesterol, and controlling blood pressure, seem to be more signiﬁcant. Many attempts to show that opening a narrowed artery saved lives or prevented heart attacks were unsuccessful, but the call for aggressive intervention was not affected.
One issue raised by the widespread misconception that the infec- tious diseases have been conquered is whether interest in public health and preventive immunizations can be sustained without the threat of epi- demics and direct experience of so-called childhood diseases. In wealthy, industrialized nations few individuals recall the heavy toll once taken by tuberculosis, diphtheria, smallpox, measles, and polio. Moreover, many people mistakenly believe that antibiotics can cure all infectious diseases. Some observers warn that the declining status of state and city public health departments indicates that, in the absence of fear, the essential, but generally routine work of such institutions is neither understood nor appreciated.
As Rudolf Virchow (1821–1902), the founder of cellular pathology, warned his bacteria-hunting colleagues, simplistically attri- buting contagious diseases to bacteria ‘‘hinders further research and lulls the conscience to sleep.’’ At the turn of the century, fear of biological ter- rorism and the threat of newly emerging diseases stimulated concerns about the ability of industrialized nations to respond to particularly viru- lent, contagious, and unfamiliar infectious diseases. According to public health experts, concern did not necessarily lead to funding and planning.
Understanding the tensions that result from changing patterns of health, disease, and demography, and the differences in patterns found in the wealthy nations and impoverished nations requires familiarity with history, geography, ecology, and economics, as well as knowledge of medicine and science. The global spread of AIDS, which has devastating villages and cities in Africa where the disease may have originated, revealed the necessity for a global and historic perspective. AIDS ﬁrst appeared as a diagnostic entity in 1981 when the Centers for Disease Control began to report that strange clusters of illnesses usually associ- ated with a severely compromised immune system were appearing in previously healthy gay men in New York and Los Angeles.
In 1984, the causative agent, a retrovirus referred to as the human immunodeﬁ- ciency virus (HIV), was identiﬁed. Within ﬁve years of the ﬁrst reports, the United States Public Health Service estimated that more than a mil- lion American were infected with HIV. Further studies of HIV suggested that the virus had not simply appeared in the 1980s, but had been incu- bating as a silent epidemic in areas of the world where the deaths of chil- dren and young adults from fever and diarrheal diseases were not at all uncommon. Presumably, other still unrecognized diseases and patho- gens remain submerged among the fevers of unknown origin (FUOs) in the developing world.
Unlike Thomas McKeown (1911–1988), the eminent social philoso-pher of medicine, who contended that medical intervention had little effect on mortality rates and minor consequences for morbidity, some medical historians believe that public health measures played a very signiﬁcant role in the control of infectious diseases during the nineteenth century. Some critics of modern medicine have argued that the term
‘‘healthcare’’ is a misnomer. Many wealthy countries actually have cre-ated what should more accurately be called an ‘‘illness subeconomy’’ that consumes a substantial and increasing share of gross domestic product in order to deal with chronic illness. Many scholars agree that there is little evidence that therapeutic medicine affected mortality and morbidity rates. McKeown’s work, summarized in The Modern Rise of Population (1976), challenged then prevailing assumptions about the relationship between medical practice and changing patterns of mortality and morbidity. Between 1800 and 2000, life expectancy at birth rose from about 30 years to a global average of 67 years. In the wealthy, industrialized nations, life expectancy at birth was more than 75 years. Although patterns of morbidity and mortality have undergone remarkable changes in this relatively brief period of human history, major differences in patterns of disease and life expectancy separate the wealthy nations from developing nations. Moreover, the so-called developing world accounts for about 80 percent of global population. In Africa and other parts of the developing world, over 60 percent of deaths are caused by communicable diseases. In Europe only eight percent of deaths are due to communicable diseases.
Perhaps the fears generated by AIDS will reverse the tendency of the wealthy nations to assume that the infectious diseases have been conquered and that the contagious diseases of third world countries are inconsequential. AIDS has made it clear that the most powerful chemotherapeutic agents are ultimately powerless against the onslaught of germs if the natural immunological defenses cannot participate in the battle. Expensive, complex new drug regimens have transformed AIDS from a fatal disease to a chronic disease, at least for those who can afford therapy, but the remedies themselves are not without risks and adverse effects. Of course, in much of the world old enemies, such as tuberculosis, malaria, measles, cholera, and, above all, poverty and mal- nutrition, have not given up their role as ‘‘million-murdering death.’’ Medical errors have become the subject of extensive studies and of sharp debates since the 1990s. Although the Hippocratic texts reveal an appreciation of the problem of medical errors and the fact that medical interventions frequently led to unintended adverse effects, recent critics of modern medical practice have diagnosed what they called a ‘‘terrify- ing epidemic of medical mistakes.’’ In 1999, the Institute of Medicine of the National Academy of Sciences published a report entitled To Err is Human, which estimated that about 100,000 Americans died annually as a result of medical mistakes that occurred in hospitals, including about seven thousand deaths attributed to medication errors and adverse drug reactions. Some experts are sure that these numbers are underestimates.
Adverse drug reactions are compounded by unanticipated inter-actions between drugs, dietary supplements, and foods, and the prob- ability that toxic reactions to particular drugs will not be detected until large numbers of people have taken a new drug for a signiﬁcant amount of time. Pharmaceutical companies and researchers have coined a new term, theranostics (diagnostics þ therapy) to suggest a strategy for combining diagnostic tests with targeted drug therapy. Diagnostic tests that could identify patients most likely to be helped or damaged by new medications would be combined with drug therapy that targets a speciﬁc gene or protein. Since the turn of the century, several such tests have been developed for use in the diagnosis and treatment of leukemia, breast cancer, colorectal cancer, and lung cancer. Skeptics note that, although ‘‘personalized medicine’’ is an admirable goal, drug companies are more likely to pursue drugs that treat many people than drugs that are speciﬁc to much smaller groups of patients. Advocates of theranos- tics argue that increased efﬁcacy and safety would stimulate the devel- opment and approval of many more new drugs for chronic diseases and infectious diseases as well as cancers.
Despite sophisticated diagnostic imaging, there is compelling evidence that many errors occur in diagnosis, surgery, and prescriptions. A report published in 2004 found that out of some sixty-four thousand patients who had undergone appendectomies between 1987 and 1998 about 15 percent did not have appendicitis. Among the female patients in this group about 23 percent of the appendectomies were unnecessary. Researchers found that cardiologists missed evidence of signiﬁcant heart disease about a third of the time. Similar errors were found in reviews of radiologists examining mammograms. Cynics say that the true extent of medical errors is impossible to measure because serious mistakes are buried with the patient, as demonstrated by studies of randomly selected autopsies. Nevertheless, biomedical scientists continue to believe that further advances in technology will provide more sophisticated and accurate diagnostic information. Skeptics insist that techniques that work in the laboratory do not necessarily work under more complex, less structured conditions.
As demonstrated in the controversy that erupted when salvarsan was used to treat syphilis, evaluating the safety and efﬁcacy of any drug or medical innovation entails many difﬁculties, scientiﬁc and political. Indeed, the passage of time and rigorous statistical analyses are likely to demonstrate that various ‘‘miracle drugs’’ are dangerous, ineffective, or no more effective than older remedies. Worse yet, some drugs pose dangers not only to the patients for whom they were prescribed, but also for their future children, as demonstrated by the tragic cases of thalidomide and diethylstilbesterol (DES). DES, a synthetic estrogen, was widely prescribed from the 1940s to the 1970s, in the mistaken belief that it would prevent miscarriages. Not only did DES increase the risk of complications during pregnancy, it caused a rare form of cancer in DES daughters, reproductive disorders in both DES sons and daughters, and increased the risk of various cancers in women who had taken the drug.
During the 1950s, thalidomide entered the German pharmaceutical market as a remedy for insomnia, tension, and morning sickness. The drug was described as more effective and safer than barbiturates. It was so commonly used to sedate children that it was often referred to as the West German baby-sitter. By 1960, when the drug was already available in about ﬁfty countries, members of the German Society for Pediatric Medicine were discussing a suspiciously high number of unusual birth defects. Ultimately, researchers estimated that about ten thousand children were born with abnormalities of the internal organs as well as deformities of the arms, legs, hands, and feet that were grouped together as phocomelia (from the Greek for seal þ limb). Widukind Lenz (1919–1995), a pediatrician and professor at the Uni- versity of Hamburg, became particularly interested in possible links between phocomelia and thalidomide. In 1961, he reported his suspi- cions about ‘‘a frightening increase in deformities’’ and suggested a link between the birth defects and a new drug.
Eventually, thalidomide was identiﬁed as a powerful teratogen (an agent that causes malformations in an embryo or fetus) and the cause of the worldwide epidemic of phocomelia. Because of the work of Frances Kathleen Oldham Kelsey (1914–), a medical ofﬁcer at the Food and Drug Administration, less than 20 cases occurred in the United States. The Pure Food and Drug Act of 1906 established the regulatory agency that became the Food and Drug Administration in order to protect consumers from dangerous foods, drugs, and cosmetics. In 1937, for example, the Masengill Company prepared a liquid form of sulfanilamide by dissolving the drug in diethylene glycol, which is a sweet, but highly toxic liquid. About 240 gallons of ‘‘sulfanilamide elixir’’ were distributed, without any tests for safety, and at least 107 people died. This tragedy created demands for federal regulations that would prevent the marketing of unsafe pharmaceutical products. On June 15, 1938, President Franklin D. Roosevelt signed into law the Food, Drug and Cosmetic Act.
Despite claims by the manufacturer, Richardson-Merrell Inc., that no adverse effects occurred when thalidomide was taken for insomnia, nervous tension, asthma, and relief of nausea in early pregnancy, Kelsey delayed approval of thalidomide by repeatedly requesting addition tests and information. Merrell was seeking approval of thalid- omide as a sleeping aid, but Kelsey noted that the drug did not make experimental animals sleepy. Despite evidence from England that some patients taking thalidomide experienced serious effects on the nervous system that resulted in tingling, numbness, and burning in their ﬁngers and toes, Kelsey’s supervisors and the drug manufacturer exerted con- siderable pressure on her to expedite approval. According to a 1962 report read into the Congressional Record by Senator Estes Kefauver, Merrell continued to call for routine approval and appealed to Kelsey’s superiors. Moreover, even without approval, the law at the time allowed Richardson-Merrell Inc. to enlist hundreds of American doc- tors to carry out ‘‘clinical trials’’ of thalidomide on their private patients. After the relationship between thalidomide and phocomelia became public knowledge, Merrell revoked its application and eventu- ally withdrew the drug from experimental use. The thalidomide tragedy was one of the factors that stimulated the passage of legislation that gave the FDA additional authority to regulate the introduction of new drugs.
An experienced researcher in pharmacology when she began work at the FDA in 1960, Kelsey had earned a master’s degree in pharma- cology from McGill University, Montreal (1934), a Ph.D. (1938) in phar- macology, and a medical degree (1950) from the University of Chicago. While teaching at the University, she married fellow faculty member, Dr. Fremont Ellis Kelsey. The Kelseys moved to South Dakota where Frances Kelsey practiced medicine and taught pharmacology. When her husband accepted a position in Washington, DC, Kelsey was hired by the Food and Drug Administration.
In 1962, after thalidomide was taken off the market by many European nations, Kelsey was lauded for preventing thalidomide birth defects in thousands of American infants. She received the Distinguished Federal Civilian Service Award from President John Fitzgerald Kennedy (1917–1963). The engraving on her presidential award reads, ‘‘Her exceptional judgment in evaluat- ing a new drug for safety for human use has prevented a major tragedy of birth deformities in the United States. Through high ability and steadfast conﬁdence in her professional decision she has made an out- standing contribution to the protection of the health of the American people.’’ The Washington Post called Kelsey a ‘‘heroine’’ and praised her for the ‘‘skepticism and stubbornness’’ that prevented a potential American tragedy. The New York Times praised Kelsey for leading ‘‘a two-year battle with the makers of thalidomide.’’ In 2000, Kelsey, who was still working in the FDA’s Center for Drug Evaluation and Research, was inducted into the National Women’s Hall of Fame in Seneca Falls, New York.
Germany’s federal prosecutor ﬁled a criminal indictment against the manufacturer of thalidomide in 1967. The complex and contro- versial trial did not end until a negotiated settlement was reached in 1970. Prosecutors agreed to drop charges against the company, and protect the company and individual defendants from future criminal or civil liability, in exchange for an agreement establishing a fund for thalidomide children. The judges explained that it was more important to improve methods of drug development in the future than to punish those associated with marketing thalidomide.
Attempts to balance the need to make drugs available with the need to prevent the adoption of drugs that are potentially dangerous remain problematic. In the 1980s, cancer and AIDS activists demanded more rapid access to new drugs. For patients with deadly diseases, they argued, the beneﬁts of new drugs outweighed any potential risks. The problem of adverse, unexpected interactions between drugs, however, is particularly likely to affect people with severe and chronic diseases. Regulatory agencies typically cite the need for constant vigilance to pre- vent future thalidomide-like tragedies, while critics of the long, slow, and increasingly expensive process of drug approval insist that new life-saving remedies are held hostage by cold-hearted bureaucrats. Few are likely to remember how Frances Kelsey, serving as a bureaucrat and a ‘‘gatekeeper’’ prevented widespread distribution of thalidomide in the United States. Complicating the argument is the realization that even a drug like thalidomide, with its notorious reputation as a terato- genic agent, may have some value in the treatment of certain diseases, including leprosy, certain AIDS-related conditions such as painful mouth ulcers and severe body wasting, arthritis and other inﬂammatory disorders, Crohn’s disease, multiple sclerosis, Alzheimer’s disease, multiple myeloma, myelodysplastic syndrome (also known as pre- leukemia), and other cancers. Thalidomide seemed to block the normal development of fetal limbs by preventing angiogenesis (the growth of new blood vessels). Obstructing angiogenesis is one of the strategies that might be valuable as a treatment for certain cancers, because like fetal limbs, tumors need new blood vessels in order to grow.
Organizations representing the surviving, adult victims of thalido-mide objected to attempts to rehabilitate this highly controversial, tera- togenic drug. When thalidomide was licensed for use in the United States in 1998, members of the Thalidomide Victims Association of Canada (TVAC) adopted the unequivocal position that they would ‘‘never accept a world with thalidomide in it.’’ Even the remote possi- bility that a drug might help victims of deadly or debilitating diseases, they warned, could lead to reckless, irresponsible, and unregulated usage, and the possibility of fetal exposure to thalidomide as well as nerve damage in adults. Rather than allowing the possibility of another generation of thalidomide victims, the Association argued for research that would lead to development of thalidomide analogs that would not have its teratogenic effects. However, the potential anticancer effects of thalidomide and its derivatives might involve the same pathways that cause phocomelia. Victims of thalidomide urged the mandatory inclusion of a picture of a thalidomide baby and other educational materials in all packages of thalidomide and the prominent use of that name along with any new trade names.
Both the idea of progress and the role of medicine become prob-lematic when morbidity and mortality are analyzed in terms of a tran- sition from the old epidemic, infectious diseases to diseases of afﬂuence and diseases of medical progress, and when patients ﬁnd their rising expectations for cure and comfort increasingly frustrated. Many scientists and physicians would agree with what Benjamin Franklin said in 1772: ‘‘It appears that the doctrines of life and death in general are yet but little understood.’’ Healthcare controversies have been addressed judiciously in professional journals and the scholarly literature, and passionately in popular books, magazines, and TV talk shows. Another ﬁve hundred pages would hardly begin to address these problems, but perhaps even a bare survey of the history of medicine will provide some of the facts and concepts that every person needs to know in order to appreciate the complex relationships among disease, health, medicine, and society. The biomedical sciences are certainly entering a new era in the development of vaccines and therapeutic agents. But as always, there are no remedies without risk. Therefore, the words of the wise doctors of Salerno still provide an appropriate conclusion to any con- siderations of the history of medicine:
And here I cease to write, but will not cease To wish you live in health, and die in peace; And ye our Physicke rules that friendly read, God grant that Physicke you may never need.