Stanford University School of Medicine and the Predecessor Schools: An Historical Perspective
Part I. Background History & E.S. Cooper's Midwestern Years

From the time when Dr. Elias Cooper began to practice medicine in Illinois in the early 1840's, his professional outlook and actions reflected the medical environment within which he pursued his career. Therefore, if we are to assess his limitations and achievements, and those of the medical college he founded, we must be familiar with the state of medical knowledge and the public health in his day.

As to the public health, It is well to remember that throughout the period of colonization and westward migration, infectious diseases were a more serious menace to the early settlers than all other hazards of their rigorous lives. For example, immigrants from England to America in the 1600's were nearly driven out by disease before they gained a foothold on the eastern coast of the continent. The first permanent English colony, established at Jamestown, Virginia, in 1607, consisted of 104 men and boys. Within six months 51 had died of disease and starvation.^[1] As previously mentioned, the second permanent English colony was founded by the Pilgrims who landed at the present site of Plymouth on the shore of Massachusetts Bay in 1620. They were a party of 102 men, women and children. Soon after their arrival "the great sickness" descended upon them and within six months 62 had died.^[2] The principal cause of the high rate of illness and death among these and later settlers was rampant infection that spread rapidly because of poor sanitation, inadequate shelter and malnutrition. No one then knew that microorganisms or "germs" existed and were the cause of infection, and there were of course no effective preventive or treatment measures.

Furthermore, the cause of infection and the principles of prevention and treatment were still unknown 200 years later when immigrants, including the Cooper and Lane families, poured into the Northwest Territory in the early 1800's. Soon thereafter it was recognized that a mysterious and often lethal fever was prevalent among the settlers, especially in Illinois but also throughout the Ohio and Mississippi Valleys. Reliable statistics are not available but contemporary reports of widespread febrile illness are convincing. In the fall of 1823 Ohio newspapers reported that more than half of the 165,000 people living within fifty miles of Columbus were ill. James Flint, an English traveler, wrote that in the fall of 1820 one-third of the inhabitants of Vincennes, Indiana, and the neighboring countryside were sick in bed. Fevers of one kind or another were so frequent and severe around Indianapolis, Indiana, in the summer and fall of 1821 that an estimated one eighth of the population died. Six months later, the Indianapolis Gazette stated that 900 of the 1000 townspeople were or had been sick.^[3] In Pike County Illinois, located on the Mississippi River, a fierce epidemic of fever killed 80 percent of the earlier settlers during the 1820s.^[4]

Gershon Flagg, an English immigrant writing in 1819 from Edwardsville in southwestern Illinois about ten miles east of the Mississippi, echoed the sentiments of many settlers in the river valley:^[5]

A letter from a correspondent in the fertile valley of the Sangamon River in central Illinois not far south of Peoria, written in about 1825, included the following comment:^[6]

This "fever", so baffling to the doctors of the region, occurred chiefly in marshy locations along the many rivers and creeks where there were clouds of mosquitoes. The illness struck mainly in the fall of the year and was characterized by episodes of chills (ague), fever and sweating that tended to recur at regular intervals of from daily to every 48 or 72 hours (i.e., quotidian, tertian or quartan). Although usually subsiding spontaneously within a few weeks or months, it often followed a chronic, debilitating and sometimes fatal course with intermittent seasonal relapses over a period of years, reducing the patient to a pale, wasted and lethargic invalid. Malignant, fulminant variants of the fever were also not infrequent, resulting in prostration, coma and death within a few days.^[7][8]

The menacing fever to which we refer was malaria. It was the scourge of the Northwest until late in the 1800's, and the most important endemic disease from the standpoint of prevalence the world has known from antiquity to the present day. Ancient writers described its typical intermittent episodes of chills and fever. A Chinese scholar spoke of its recurrent paroxysms three thousand years ago. Hindu sages in India recognized the disease. Hippocrates (460-370 B.C.) wrote of it as common in Greece in the fifth century B.C. Alexander the Great (356-323) died of a fever in Babylon at the age of 33. It was probably malaria.^{[9][10][11][12]}

Although present as a devastating pestilence throughout Eurasia and Africa from the earliest historic times, the New World was free of malaria until around 1500. At about this time it was brought to the Americas from Europe and Africa by the Spaniards and their slaves whose red blood cells, infected with the malarial parasite, were taken up by the bite of the ubiquitous Anopheles mosquitoes and transmitted thereby to an endless chain of human carriers.^[13] The disease was unknown among the Indians in the Ohio Valley and the Northwest until after the arrival there of European immigrants. In Illinois, the incidence of malaria was at a low level from the first settlements in about 1700 until 1760 when it rose within a decade to epidemico-endemic proportions and held that position for about 80 years. It then began a slow decline in the 1850's, and virtually disappeared from the state by 1900.^[14]

From this brief introduction to malaria as the major health problem in Illinois and the Northwest in the 1840's, we can turn for further insight into the contemporary state of medical knowledge to Drake's discourse on Principal Diseases of the Interior Valley of North America, 1850^[15] In this comprehensive, landmark study which we cited earlier, Drake states that the common endemic fever of his day (which we now know as malaria) was variously called autumnal, bilious, intermittent, remittent, congestive, miasmatic, malarial, marsh, malignant, chill-fever, ague, fever and ague, dumb ague or , simply, "the Fever". The number of names for the disease reflects the confusion over its etiology and behavior. Drake prefers to call it "autumnal fever."^[16]

Keeping in mind that it was still unknown in Drake's time that microorganisms were the cause of infectious diseases, we can appreciate his problem in trying to explain the origin of this troublesome fever. He calls attention to the following three possibilities. He first mentions the Meteoric Hypothesis whose advocates ascribed the disease to the combined action of a hot, humid and electrical atmosphere. They claimed that these conditions alone were sufficient to cause the fever, and they did not accept the idea that a "special agent" of some kind was involved in its induction or spread. Drake himself rejected the meteoric concept.^[17]

He next discusses the Malarial Hypothesis which was based on the commonly held opinion that the agent responsible for the fever was a noxious gas (malaria in Italian) exuding from decaying organic matter such as found in swamps and other wetlands. In support of this view Drake points out that "heat, water, and dead vegetable and animal forms" have been shown always to be present wherever autumnal fever prevails. Yet, he cautions, "while the conditions under which autumnal fever appears are sufficiently clear to observation, the existence of a special gaseous agent, resulting from them, remains to be proved."^[18]

Finally, Drake presents his own Vegeto-Animalcular Hypothesis, explaining that:^[19]

Being aware that microscopists were then describing a variety of tiny life forms, Drake goes on to postulate that the fever results when these microscopic "animalcules" or vegetable "germs" are introduced through the lungs into the blood. There they act as a noxious agent on the solids of the blood and on the vast internal surface of the circulatory system to produce an irritability or inflammation manifested in the patient by the characteristic symptoms of the disease.

He concludes by saying: ^[20]

These speculations of Drake in 1850 regarding the cause of malaria, although very astute for his day, are evidence of the limited scope of medical knowledge only 150 years ago with respect to infectious disease, the major cause of illness and death worldwide. The 1850's were also the period when Elias Cooper practiced surgery in Peoria and planned his move to San Francisco where he inaugurated medical education on the Pacific Coast.

In retrospect, it is clear that Drake's work on malaria and Cooper's Peoria interlude coincided with a mid-century watershed in medical history. In so far as one can determine the chronology of such an occurrence, it was at about this time that medicine entered its Modern Era. European and American medicine were emerging from their preoccupation with baseless medical systems and useless traditional remedies. Theoretical doctrines were being subjected for the first time to scientific scrutiny. Conventional therapy such as blood-letting was being evaluated by objective clinical studies, often involving the correlation of bedside and autopsy findings, a process then diligently pursued in the large urban hospitals of Europe. Most importantly, there was an increasing flow of information and discoveries from the new basic sciences of microscopic anatomy, physiology, pathology and pharmacology.^[21][22]

As a means of shedding further light on this momentous change, now recognized as the renaissance of medicine, we shall review that breakthrough which had the greatest significance for mankind - conception and verification of the germ theory - a subject to which we have already been introduced by Dr. Drake. How better to demonstrate the slow progress of medicine, and the humble state of medical knowledge in 1850, than to trace the evolution of the germ theory from Fracastorius in the 16th century to Pasteur, Lister and Koch at the end of the 19th, 300 years later? Certainly Cooper's contributions will be more fully understood and appreciated when viewed against the backdrop of historic medical events that had boundless implications not only for the public health, but also for medical education.

The vegeto-animalcular hypothesis was not original with Drake but evolved through a succession of observations beginning with those of Heironymus Fracastorius of Verona. Educated at Padua, he was a renaissance man of many talents, and was acclaimed as an astronomer, geographer, botanist, mathematician, philosopher, poet and physician. It is from his poem on Syphilis that the name of that disease is derived. In his greatest work on Contagion, dating from 1546 and before the invention of the microscope, he advanced the theory that many diseases are caused by transmissible, self-propagating entities called "germs". He conceived of these "germs" not as living organisms but as chemical substances that could evaporate or diffuse in the atmosphere, and spread from person to person by direct contact, by fomites or by transmission at a distance. He postulated that each disease is specific and is caused by a specific "germ" that propagates itself in the tissues of the infected host, causing the disease by setting up chemical, putrefactive changes in those tissues. These and other features of Fracastorius's theory of contagion are remarkably modern except for his idea that "germs" were chemical substances rather than living organisms.^[23]

The invention of the microscope by Galileo in 1609 revealed a previously invisible world full of tiny objects which fascinated the scientists of the time. Athanasius Kirchir, a German-born Jesuit priest, had a primitive microscope with which he thought he found living organisms or "worms" not visible to the naked eye in fluid from the dead bodies of plague victims. Since his microscope could not possibly have visualized bacteria, the swarming microscopic animals (animalcules) which he described as "worms" were probably insect larvae or rouleaux of red blood-corpuscles. Nevertheless, it is significant that Kirchir went on to conclude (erroneously) in his treatise Scrutium Pestis of 1658 (On the Origin, Causes and Behavior of Plague) that plague was transmitted from person to person along lines already laid out by Fracastorius, but with the altered premise that the infecting agent was living effluvia rather than a chemical substance (It was not until the 1890's that the plague bacillus was identified and its transmission by rat fleas demonstrated.)^[24] In any case, Kirchir may be credited with the first really effective presentation of the theory that living organisms are the primary cause of infectious disease. There is, however, yet another major flaw in Kirchir's concept of contagium animatum (living contagion). He believed that the living germs of disease were spontaneously generated in decomposing organic matter - a question not resolved until the theory of spontaneous generation was ultimately demolished by Pasteur late in the 1800's.^[25]

The widely held concept of spontaneous generation was at least questioned but by no means seriously challenged by the experiments of the Italian Francesco Redi. Born at Arezzo, he graduated at Pisa in medicine and philosophy in 1647, and practiced with great success as a physician in Florence. He was also a poet, philologist and naturalist of note. His major contribution to science was Experiments on the Generation of Insects (1668) in which he reports that when flies are allowed to swarm on meat in a jar, maggots appear in the meat as if by spontaneous generation; whereas, when a gauze is placed over the mouth of the jar, forcing the attracted flies to swarm on the gauze, they lay eggs on the gauze and there the maggots form. Meanwhile the meat within the jar putrefies but produces no maggots. These and similar experiments led Redi to conclude that in all cases where living matter is apparently produced from dead matter, the real explanation is that seeds of the animals or plants generated in the dead matter have been introduced from the outside. The doctrine of biogenesis broached by Redi's simple experiments began thereafter to gain some acceptance. Nevertheless, majority opinion for the next 200 years continued to favor the dogma of spontaneous generation of putrefaction and infection, thus bearing witness to the glacial pace of change in the scientific world prior to the mid 19th century.^[26]

It remained for Antony van Leeuwenhoek, a draper by trade in Delft, Holland, with superior microscopes of his own construction, to discover the entirely new world of bacteria, and provide for the first time an objective basis for the theory of a "living contagion". This self-trained amateur microscopist, who created microscopes surpassing all those hitherto devised, regularly communicated his findings to the Royal Society of London. His Letter 18 (October 9, 1676) to the Royal Society is the classic document in which not only were protozoa described, but bacteria were also clearly seen and unmistakably identified as "incredibly small; nay, so small in my sight, that I judged that even if 100 of these very wee animals lay stretched out one against another, they could not reach to the length of a grain of coarse sand". Although Leeuwenhoek himself did not associate these "wee animals" with the causation of disease, others began to do so, but only in theory.^[27]

We can now see that both the concept of contagion by living organisms (the germ theory of disease), and a promising direction for basic research into that vital issue (by use of the microscope), had emerged by 1700. Nevertheless, proof of the germ theory was delayed for over 150 years until the microbial origin of infection was conclusively established by the work of Pasteur, Lister and Koch.

Meanwhile, during the long century and a half between Leeuwenhoek and Pasteur, physicians like Drake continued to search for an explanation of contagion and for a method to control it. Among these physicians were two whose contributions have earned them the distinction of being considered forerunners of Lister in their successful clinical approach to the prevention of an infection. They were Oliver Wendell Holmes of Boston and Ignaz Philip Semmelweis of Vienna. Their deductions about the contagiousness of puerperal fever brought them to the threshold of affirming its microbial origin - a threshold that Lister was later able to cross as a result of Pasteur's discoveries.

In 1834, at the age of 34, Oliver Wendell Holmes wrote a paper on The Contagiousness of Puerperal Fever in which he convincingly argued that the infection was often transmitted to the patient by her attendants. In addition he laid down sound procedures for preventing the spread of the contagion. In retrospect, his treatise stands as an historic landmark, not because of any original observations, but because of the clarity and forcefulness with which he addressed both the transmission and prevention of this devastating disease - a disease now known as "postpartum endometritis", and so well controlled by asepsis and antibiotics as to be rarely life-threatening. In modern form it bear no resemblance to the fierce and consuming pelvic sepsis of the pre-Listerian era. Then it was usually an overwhelming infection, commonly sudden in its onset within a few days after delivery with chill, fever and prostration, and often as rapidly lethal. It occurred both sporadically and in epidemics, mortality reaching near 100 percent in small clusters of "malignant" infection, and up to more than 35 percent in some epidemics. As a threat to all young mothers it was the destroyer of families, and a most dreaded pestilence.^[28]

Holmes's interest in puerperal fever came about by chance. He graduated from Harvard Medical School in 1836 and served as Professor of Anatomy and Physiology at Dartmouth College from 1838 to 1840. He then returned to Boston where he went into general practice and became a member of the Boston Society for Medical Improvement. At one of the Society's meetings a report was read that concerned a physician who did a post mortem examination on the body of a woman who had died of puerperal fever. The physician himself died of infection in less than a week, apparently in consequence of a wound received while doing the autopsy. During the interval between receiving the wound and dying from it, the physician delivered several women, all of whom developed puerperal fever.

Based on his conviction that the physician had transmitted the contagion of puerperal fever from the deceased woman to the women he delivered, Holmes stated the following general principle:^[29]

This concept was by no means new, as Holmes illustrated by citations from the medical literature, mainly British journals, which he reviewed thoroughly. He found numerous accounts of epidemics of puerperal fever, and many reports of multiple cases of puerperal sepsis occurring in the practice of a specific doctor, midwife or nurse. Frequently, the presumed carrier of the contagion had an immediately prior exposure to puerperal sepsis in another patient or at an autopsy, or to a patient with erysipelas or peritonitis. In addition to reviewing the literature, Holmes consulted older and more experienced practitioners in Massachusetts who informed him of similar outbreaks of puerperal fever in the practice of individual physicians in their areas.

As an example of the spread of puerperal fever by contagion, Holmes referred to a paper widely quoted in the medical literature of his day: "A Treatise on the Epidemic Puerperal Fever of Aberdeen" published in 1795 by Dr. Alexander Gordon who treated 77 cases of puerperal fever (with 28 deaths) in Aberdeen, Scotland, during the two year period from December 1789 to March 1792. Dr. Gordon wrote:^[30]

In support of his thesis that puerperal fever is contagious Holmes also made reference to more than twenty other authors whose views conformed with his own and those of Dr. Gordon.^[31] Among them was the distinguished James Blunder, Professor of Obstetrics and Lecturer on the Diseases of Women at Guy's Hospital. The following excerpt from Blundell's Lectures on Midwifery, as quoted by Holmes, reflects the lingering uncertainty in the 1840's, even among some of the highest authorities, as to the contagiousness of puerperal fever:^[32]

Blundell, in his textbook on The Principles and Practice of Obstetricy, has little more than this to say regarding the control of the spread of puerperal fever: "As to its prevention, I know of nothing certain."^[33]

Holmes, having gathered exhaustive and thoroughly convincing evidence of the contagiousness of puerperal fever, was doubtless gratified to find himself in agreement with the majority of contemporary British authors on the subject. Nevertheless, he learned that some eminent obstetricians did not agree with his conclusion. For example, in the course of his research he discovered in the Quarterly Summary of the Transactions of the College of Physicians of Philadelphia for May, June and July of 1842 the report of an on-going epidemic of puerperal fever in Philadelphia in which there were egregious examples of cases traceable to single physicians.^[34]

One of these Philadelphia physicians, a Dr. Rutter, had some 70 cases of puerperal fever with 15 deaths during a period of less than 12 months during 1842 - a number rivaling the 77 cases in two years in the Aberdeen epidemic reported by Dr. Gordon. Moreover, it immediately caught Holmes's eye that Dr. Charles D. Meigs, Professor of Obstetrics at Jefferson Medical College, had consulted on some of Dr. Rutter's patients. Professor Meigs was aware that Dr. Rutter had a far greater number of such cases than any other practitioner in Philadelphia, but considered this due to the fact that he had a large practice.^[35] Holmes took special note of Meigs's viewpoint and made it plain in his paper that this was an outrageous conclusion to be reached by a professor of midwifery who, in the face of a raging epidemic of puerperal fever in Philadelphia, made no reference to the contagiousness of the disease, and attributed its grossly epidemic proportions in Dr. Rutter's private practice to coincidence. Meigs's failure to recognize the role of contagion in the epidemic is particularly surprising since he had recently (in 1842) edited a monograph on puerperal fever that included the treatises of Dr. Gordon and three other well known British obstetricians, all of whom commented on its communicable nature.^[36]

In any event, Meigs refused to acknowledge the contagiousness of puerperal fever and took strong exception to Holmes's sharp criticism of his position on the matter. There followed an acrimonious exchange in which Meigs attacked Holmes in disparaging language to which Holmes replied: "I take no offense and attempt no retort. No man makes a quarrel with me over the counterpane that covers a mother, with her new-born infant at her breast! There is no epithet in the vocabulary of slight or sarcasm that can reach my personal sensibilities in such a controversy."^[37] Holmes gave not an inch of ground in the dispute that continued for over a decade. The judgement of posterity has since been harsh on Professor Meigs who stated that "(I prefer) to attribute these cases (of puerperal fever) to accident, or Providence, of which I can form a conception, rather than to a contagion of which I cannot form any clear idea, at least as to this particular malady."^[38] The 1842 edition of Meigs's widely acclaimed textbook entitled The Philadelphia Practice of Midwifery makes no mention of the contagiousness or the prevention of puerperal fever. It was as though the extensive and compelling contemporary literature on the subject did not exist. The mind of the Dean of American Obstetrics was completely closed.^[39]

As was the mind of Hugh L. Hodge, Professor of Obstetrics at the University of Pennsylvania in Philadelphia, who also denied the contagiousness of puerperal fever and assured his students that they, as physicians, could never be the minister of evil to convey a horrible virus to their parturient patients.^[40] Thus Holmes had the two most influential professors of obstetrics in America aligned against him.

Prevention of puerperal fever in the pre-microbial era was based on the assumption that an unknown contagion existed in the lying-in premises, or was carried to the childbed by an attendant of the mother. Holmes did not indulge in speculation (as did Drake) regarding the nature of the contagion, but assumed the physical presence of an unseen, transmissible agent. Years later, in 1894, Holmes said he was pleased to remember that "I took my ground on the existing evidence before a little army of microbes was marched up to support my position."^[41]

As to preventive measures within lying-in hospitals, the British medical literature of the day called for strict cleanliness of bedding and wards, and good ventilation to combat epidemics. If these measures failed, the ward should be closed and the patients relocated. Outbreaks of puerperal fever were not unusual in lying-in wards and, on that account, some obstetricians were convinced that the loss of life from puerperal fever occasioned by lying-in institutions completely defeated the object of their founders. Although he does not prescribe a specific regime for the decontamination of hospitals, Holmes stresses the danger of spread of contagion within that environment.^[42] Among others, he refers to the observations of Dr. Edward Rigby, Physician to the General Lying-in Hospital and Lecturer on midwifery at St. Bartholomew's Hospital in London:^[43]

As to preventive measures applicable to personnel, many authors recommended procedures to be observed by accoucheurs and other attendants in order to avoid spreading the contagion. The following are examples of such recommendations.

In 1795 Alexander Gordon, MD, Obstetrician at Aberdeen, Scotland, suggested:^[44]

In 1817 William Hey, Esq., Surgeon of the General Infirmary at Leeds, England, wrote:^[45]

In about 1814 John Armstrong, MD, Obstetrician at Sunderland, England, had this brief comment:^[46]

In 1833 Robert Lee, MD, Obstetrician at the British Lying-in Hospital in London, proposed:^[47]

In 1841 Dr. Rigby of St. Bartholomew's in London issued an emphatic warning:^[48]

Now consider, in relation to all of the above, the following protocol framed by Holmes:^[49]

Holmes concluded his paper with these eight unambiguous rules of conduct for the accoucheur. Compared to guidelines in the existing literature, examples of which were cited above, Holmes's precepts were comprehensive, explicit and uncompromising. They were the most definitive standard yet published on the prevention of a fearsome and seemingly capricious disease. Respect for his protocol's eight enduring principles, ignored for decades by prisoners of false doctrines such as the Philadelphia professors, saved countless lives around the world.

There are other reasons for the historic significance of Holmes's essay. As we have seen, during the previous 50 years numerous epidemics of puerperal fever had been studied and reported by a new generation of British physicians. They had abandoned traditional medical dogma for a scientific approach involving correlation of clinical course with post mortem features. It was at this juncture that Holmes fortuitously became interested in the problem. Without burdensome preconceptions, he reviewed the available reports and recognized that they provided incontrovertible evidence of the contagiousness of puerperal fever. More importantly, he convincingly traced the contagion's common mode of epidemic spread to the physicians and others who attended the patient.

By this time the concept of a transmissible "contagion" of some kind as the agency of infection in puerperal fever had gained some but by no means general acceptance. There was still much equivocation and denial in high places, and widespread ignorance among practicing physicians of the risk of contagion. To Holmes's New England conscience, there was lacking in the medical community at large a proper sense of outrage and urgency over the propagation of a preventable calamity, and it was inexcusable.

Far from avoiding the implications of this conclusion, Holmes analyzed existing evidence and, in a persuasive treatise that for cogency and eloquence is at once both a medical and a literary classic, he defined the obligations of all who attend at childbirth. It has been rightly observed that Holmes was not an obstetrician nor had he done independent research on his subject, but he was the first to give unmistakably clear and credible voice to the emerging consensus that puerperal fever was contagious, a specific infection often conveyed by doctors and nurses. His achievement was to create a synthesis of existing observations and ideas from which he evoked a momentous conclusion - no longer could there be any question of the contagiousness of this terrible affliction, or of the human agency in its dissemination. For this historic contribution Holmes deserves to be honored as an illustrious pathfinder in world medicine.

Unfortunately, circumstances prevented the early and wide distribution of Holmes's paper that its importance merited. The paper was originally an essay read before the Boston Society for Medical Improvement. At the request of the Society, the essay was printed as a paper in the New England Quarterly Journal of Medicine and Surgery for April 1843. As this journal never had a large circulation and was discontinued after one year, the paper was not brought fully to the attention of physicians or the public. That it was not entirely unnoticed is shown by favorable reference to it in 1852 in the highly regarded Dictionary of Practical Medicine by James Copland, MD, Consulting Physician to Queen Charlotte's Lying-in Hospital in London. In affirming his belief in the infectiousness of puerperal fever, Dr. Copland pointed out that "Dr. Holmes has forcibly and eloquently brought this much neglected subject before the profession." But Copland also reminded his readers that the contagiousness of puerperal fever was still denied by such established authorities as Hulme, Leake, Hull, Beaudeloque, Tonnellé, Dugé, Dewees and others.^[50]

In 1855, twelve years after its original appearance in the New England Quarterly, Holmes reprinted his essay ,"without the change of a word or syllable", as a private publication under the title of Puerperal Fever, as a Private Pestilence. He was led to do so by his disappointment over its limited distribution originally, and by his conviction as to the continuing importance of warning refractory members of the profession of the contagiousness of puerperal fever. On a more personal level he was offended by the disparaging remarks of Dr. Meigs, and appalled by the pompous denial by the Philadelphia professors of the infectious nature of this terrible disease, a truth that the "commonest exercise of reason" should reveal. Holmes prefaced the reprint with a masterful Introduction in which he aired all these issues, deflated the pretensions of the professors, and warned medical students of the sophistry in their arguments.^[51]

By the time his essay was reprinted in 1855, Holmes had joined the Harvard medical faculty as Parkman Professor of Anatomy and Physiology, a post that he held for 35 years from 1847 to 1885 (the chair of Physiology was separated in 1871), after which he continued for 12 more years (1882-1894) as Emeritus Professor. He was Dean of the Medical School from 1847 to 1853.^[52] After his appointment to the Parkman professorship, Holmes gradually withdrew from the practice of medicine, but he is warmly remembered as a legendary teacher of Anatomy. His engaging style and captivating wit made him, it is said, the only professor who could keep the students awake during a 1 p.m. lecture. As the years passed, his literary affinities increasingly claimed his interest, and he became better known as a conversationalist and author than as a physician. His graceful pen earned him a respected place as poet (Chambered Nautilus) and essayist (Autocrat of the Breakfast Table) among such contemporary writers of the New England Renaissance as Emerson, Hawthorne, Longfellow and Whittier.^[53][54][55]

Nevertheless, Holmes will also be well remembered by distant posterity for his Thesis of 1843 on puerperal fever and the passion with which he defended it against all sceptics and against the entrenched error of "the teachings of two Professors in the great schools of Philadelphia."^[56]

Never had the rites of motherhood been so ably defended.

When in 1855 Oliver Wendell Holmes published the reprint of his 1843 article on puerperal fever, he provided not only an Introduction but also a supplement entitled Additional References and Cases. In this supplement he briefly reviewed journal articles and other works printed since 1843 which further documented the contagiousness of puerperal fever. Among these publications were two reports on the research in Vienna of a Dr. Semmelweis whose "doctrine" of the cause and control of epidemic puerperal fever was highly commended by the authors of the reports. Reference to these reports in his supplement was a recognition by Holmes that Semmelweis's observations, of which he was learning for the first time, were possibly of great significance - as indeed they proved to be.^[57][58]

Semmelweis, of German ancestry and Hungarian birth, studied medicine at the University of Vienna where in 1844, at the age of 25 he received the degree of Doctor of Medicine. Later in the same year he qualified for the degree of Master of Midwifery, and from that time forward devoted the remainder of his life to the science and practice of Obstetrics. Upon receiving his Master's degree he at once applied for the position of Assistant in the Lying-in Division of the huge Vienna General Hospital (Das allgemeine Krankenhaus), and was eventually appointed to that post.

The General Hospital's Lying-in Division was the largest of its kind in the world. It was also one of the most deadly due to prevalence among its postpartum patients of what was known as "the endemic puerperal fever of Vienna."[59] James Simpson, eminent British obstetrician and father of chloroform anesthesia, pronounced this censure of the situation in Vienna. He said "he knew in what a lamentable condition midwifery in Germany, and especially Vienna, still remained; he knew for certain that the cause for the high mortality lay only in the unbounded carelessness with which patients were treated." Incidentally, the great Simpson completely rejected Semmelweis's discoveries.^[60]

The sensitive and deeply humanitarian Semmelweis was appalled by the death rate from puerperal fever in the Lying-in Division, and search for the cause and control of this pitiless disease became his life's work. For a laboratory he had the First and Second Obstetrical Clinics, each averaging about 3000 deliveries per year. When he tabulated the deliveries and deaths by month and year in each of the Clinics for the six-year period from 1841 to 1846, he found that First Clinic, where medical students were trained, had a death rate from puerperal fever of 9.9%; whereas, the death rate in Second Clinic where midwives did the deliveries was 3.3% - only one-third that of First Clinic. It would be too chilling to list the grotesque explanations offered by the medical "authorities" and a government commission in Vienna to account for the evil reputation of First Clinic where patients were in mortal fear to go because they believed that a doctor's interference was always the precursor of death.^[61] Johann Klein, the reactionary Professor of Obstetrics who presided over the upsurge of puerperal fever which Semmelweis found so disturbing, ridiculed the theory that the disease was contagious.^[62]

These circumstances were especially troubling to Semmelweis for he himself had been in charge of the First Clinic since February of 1846, and the high death rate persisted in spite of all his efforts. He had studied the problem from every angle in the wards. He also frequented the pathology department where he participated in the post mortem examinations of the many victims, becoming increasingly mindful of the nauseous fetor that clung to his hands and clothes long after an autopsy. There is no indication that Semmelweis, at this stage of his career, accepted the concept of contagion as defined by Holmes of whom he was not aware until years later. Yet by 1847 there was no one in Vienna with greater knowledge of endemic childbed fever than Semmelweis, and his mind was prepared to grasp the solution to the mystery of its cause when chance provided the clue - as it soon did in the sad loss of a dear friend, Dr. Kolletschka, who died of infection.

By a singular coincidence, a physician's death from overwhelming sepsis following a simple puncture wound received while performing an autopsy created circumstances that led both Holmes and Semmelweis to their independent conceptions of the cause of epidemic puerperal fever. From time immemorial, pyemia had stalked the deadhouses as a dreaded foe of all anatomists, pathologists, surgeons and others who dissected. It was well known that a swiftly fatal infection might follow even the slightest prick of a knife or needle during anatomical dissection, autopsy, or an operation such as amputation of a gangrenous limb. Holmes in 1843 and Semmelweis four years later in 1847 both recognized the similarities between this accidentally acquired infection and puerperal fever. It was the genius of Semmelweis to derive from this observation a new principle of prophylaxis and, by experiment, to demonstrate its validity.

Jakob Kolletschka, a 43 year-old Professor of Forensic Medicine, was a former teacher and friend whom Semmelweis held in the highest esteem. Kolletschka's death early in 1847 from a scalpel wound, incurred during an autopsy, had a profound effect upon Semmelweis who assuaged his anguish by studying in detail the reports of his friend's fatal illness and autopsy. These records disclosed that after a puncture wound in his finger from the knife of one of his pupils, Kolletschka developed lymphangitis and phlebitis in the same upper extremity. From there the infection spread. He developed pleurisy, pericarditis, peritonitis, and meningitis; and a few days before his death an abscess occurred in one of his eyes. This generalized dissemination of infection was exactly the same that Semmelweis had seen at autopsy in women who died of puerperal fever. A new thought was forced upon his mind with irresistible clarity - the disease from which Kolletschka died was identical with that from which he had seen so many hundred puerperae die.^[63]

Semmelweis designated the causative agent as "cadaveric particles" that enter the circulation after being introduced by the knife in the case of pathologist's pyemia. In puerperal fever, the particles are introduced into women in labor by students and others who do vaginal examination with hands contaminated by such particles during autopsy or anatomical dissections, or during examination of patients with puerperal fever or other infections. Contaminated instruments and bedclothes might also transfer the causative agent. He also observed:^[64]

By this conjecture Semmelweis is thought by some to have foreshadowed the germ theory by proposing that, while puerperal fever is in most cases a cadaveric infection, it is sometimes traceable to other sources, i. e., to a "living organism."^[65]

Now the explanation for the higher mortality from puerperal fever in First Clinic became obvious to Semmelweis - medical students and doctors carried cadaveric particles to the patients on hands contaminated at post mortem dissections. In Second Clinic the midwives, who did no dissections, were not thus contaminated.^[66]

Since students and others could not be banned from work in the pathology and anatomy laboratories, it was necessary to establish a procedure for the decontamination of their hands. (It was not until 1890 that rubber gloves were introduced by Halsted of Johns Hopkins to protect the hands of his surgical team from irritating antiseptics.) Semmelweis associated cadaveric particles with the foul clinging odor of the autopsy and dissecting rooms, and knew that soap and water would not dispel it. However, he found a solution of chlorinated lime to be effective and therefore chose it as the decontaminant. The system of prophylaxis introduced into the regular obstetric practice of First Clinic in May 1847 was simple. Placards with the following directions were posted conspicuously in the wards:^[67]

The experiment was successful. Within a few months, the mortality rate in First Clinic was no greater than in Second Clinic, and remained so as long as Semmelweis's directions were strictly followed. In 1848, the first full year in which the chlorine-washing was carried out assiduously, 45 out of 3556 puerperae died of puerperal fever in the First Clinic for a mortality of 1.27 %. In the Second Clinic, during the same period, 43 died out of 3219 delivered, or 1.34%.^[68] These results were a clear validation of the concept and method of prophylaxis which became known as the Semmelweis "doctrine."

Far from bringing him preferment in the University, Semmelweis's discovery divided the faculty. Professor Klein, head of obstetrics, was adamantly opposed to the Semmelweis doctrine and squelched a proposal by Skoda, Professor of Chest Diseases, for a commission to evaluate its effectiveness. Believing it better to prevent contamination than to remove it, Semmelweis petitioned the authorities for a regulation preventing students occupied in the Lying-in Hospital from engaging in any dissection whatsoever. Here again, Professor Klein barred the way.^[69]

When Semmelweis's Assistantship expired in March 1849, Klein refused to renew it. Semmelweis appealed, precipitating a faculty feud between Klein and Skoda from which Klein emerged the victor, and Semmelweis the loser. Frustrated and demeaned by the rejection, he departed abruptly for Budapest in 1850 without expressing his gratitude to Skoda and others who had supported his doctrine and his quest for a position in Vienna. Semmelweis's erratic and inconsiderate behavior was never forgotten.

Soon after his arrival in Budapest, Semmelweis was made head of the obstetrical service at the St. Rochus Hospital in Pest. There he conducted a six-year clinical trial (1850-1856) of his doctrine and achieved a mortality rate of 0.85% on a maternity service where puerperal fever had previously raged. In 1855 his academic aspirations were at last gratified by his appointment as Professor of Midwifery at the University of Pest. He took over an obstetrical service in shambles and, during the first full year of his tenure, reduced the death rate from puerperal fever to 0.39 %, an unheard of record on the continent.^[70] Now full of confidence in his doctrine, he spent the remainder of his career zealously promoting it.^[71]

Unfortunately, Semmelweis did not personally author a single publication about his work until 1861. His findings were first announced to the profession at large in December 1847, not by himself, but by his good friend Ferdinand von Hebra, editor of the Journal of the Royal Imperial Society of Physicians in Vienna, who wanted to encourage him and gain recognition for him in spite of Professor Klein. The article, written by v. Hebra, was entitled "Experience of the highest importance concerning the etiology of epidemic puerperal fever at the Lying-in Hospital."^[72][73][74]

Other of Semmelweis's friends and supporters also wrote articles and tried to win adherents to his doctrine, but with indifferent success. It was two of these articles that came to Holmes's attention and were referred to by him in the 1855 reprint of his 1843 article. Finally, in 1861, Semmelweis published his magnum opus of 543 pages entitled The Etiology, Concept, and Prophylaxis of Puerperal Fever. This monograph was an exhaustive account of his studies, experience and evolving conception of puerperal fever. The Etiology documented his life's work and contained a vigorous defense of his doctrine that for the previous 14 years had been mired in controversy and counterclaims that deterred its general acceptance. In fact, to his great distress, his doctrine had been ignored or dismissed as unsound by many of the leaders in the field of obstetrics. ^[75][76][77]

Rebuffs to his struggle for wider application of his doctrine were disturbing to Semmelweis. He particularly resented attacks by the self-serving forces of the authoritarian medical establishment, and he lashed out against them. His doctrine was opposed by powerful members of the academic hierarchy such as Professors Busch of Berlin; Hamernik of Prague; Hecker of Munich; Kiwisch of Würzburg, Lumpe of Vienna; Rosshirt of Erlangen; Scanzoni of Würzburg (formerly of Vienna); and others. Mortality from puerperal fever on the services of some of these Professors of Midwifery ranged as high as a barbarous 26% (under Kiwisch at Würzburg).^[78] The damning evidence that they were themselves the remorseless messengers of death was a scarcely veiled threat to their pride and eminence. Semmelweis was unsparing in his condemnation of those who denied his doctrine in spite of the high mortality rates in their own institutions. This from his open letter to Professor Scanzoni of Würzburg who, while professor at Vienna, had disparaged Semmelweis's earliest work:^[79]

At last, although acceptance of his principles was gaining ground, the long years of controversy and intense preoccupation with defense of his doctrine affected Semmelweis's mind. Because of increasingly eccentric behavior, he was admitted to a sanatorium for mental disorders. There an infected wound on his finger, received during a gynecological operation, was discovered. Defying all efforts at control, the infection progressed to gangrene followed by extensive sepsis, leading to his death in 1865 at the age of 47. By a tragic irony Semmelweis died from the same manifestations of pyemia as his friend, Kolletschka, whose death provided the clue to the prevention of puerperal fever.

The importance of Semmelweis as a forerunner of Pasteur and Lister is in his doctrine of puerperal fever as a bloodstream infection (septicemia) caused by a specific transferable agent, and preventable by destroying the agent with an antiseptic (20 years before Lister published a description of his antiseptic principle). No one before Semmelweis had articulated a concept of the etiology and prophylaxis of this disease so consistent with all the facts as later determined. His demonstration by controlled experiment that the incidence of puerperal fever could be significantly reduced by an antiseptic method ranks Semmelweis among the foremost medical scientists of his day. The ultimate price of a broken spirit that he paid for his devotion to the spread of his life-saving doctrine ordains him as a martyr to Medicine.^[80]

The relative merits of the contributions of Holmes and Semmelweis have often been debated. Holmes, man of letters and one of the most perceptive medical thinkers in early American medicine, analyzed the experience and views of British contagionists. From these abundant data, refined by his own judgement and colored by his indignation and sense of urgency, Holmes fashioned a powerful and convincing brief in defense of women in childbirth. That puerperal fever was contagious was not the question. The extensive and horrifying evidence was undeniable. At issue was the incredible, monstrous failure of the medical profession to recognize a "momentous fact, which is no longer to be considered for trivial discussions, but to be acted upon with silent promptitude."^[81] Holmes concluded his thoroughly documented treatise with a warning that those who fail to heed its conclusions must answer at the bar of judgement for their crime; and he promulgated the most comprehensive and effective set of principles yet published to prevent the spread of the contagion of puerperal fever. Holmes made an eloquent appeal to the common sense and conscience of the profession. As such, his message was the most trenchant, timely and persuasive of its kind in the medical literature, and remains so to the present day. It unquestionably saved thousands of lives. Herein lies its merit. The life's work of Semmelweis - humanitarian, experienced clinician, dedicated scientist - is of another category and order of magnitude, and should not be compared to the treatise of Holmes. As the exponent of the most advanced concept of infection up to his time, and harbinger of the antiseptic method, Semmelweis simply has no peer.

It was not until after 1867 that Lister's antiseptic method, having proven its value in the prevention of infection in surgery, was applied with success in maternity hospitals, obstetricians in general having finally acknowledged the contagiousness of puerperal fever. According to Dr. Emile Roux, one of Pasteur's assistants, the actual cause of the disease was not revealed until 11 March 1879. On that day Pasteur was attending the Academy of Medicine in Paris and the subject of puerperal fever came under discussion:^[82][83]

Thus ended the agonizing search for the cause and prevention of puerperal fever. Vive Pasteur!

In keeping with our purpose, this account of the contributions of Holmes and Semmelweis to the control of puerperal fever will serve as a reminder of the state of the art in their time. It will also call attention to the striking contrast between the slowness with which medical advances were accepted in the mid 1800's and the readiness with which new concepts and technologies are adopted in the present day.

Much has been made of the fact that Dr. Elias Cooper was using alcohol in the management of surgical wounds as early as 1850 when Semmelweis was completing his clinical trials of chlorinated lime as an antiseptic.

In a journal article in 1929 Professor Emmet Rixford of Stanford expressed the opinion that:^[84]

In an article published the previous year, Professor Rixford stated that Cooper "washed his wounds with 25 percent alcohol."^[85]

No source is cited for these statements and it is assumed that Rixford received the information about Cooper's surgical use of alcohol from Levi Cooper Lane. The inference of Rixford's comments is that Cooper independently conceived and practiced a primitive form of antisepsis.

Perhaps he did, but we can find only such statements from Cooper himself as the following:^[86]

In another article Cooper indicates that the use of an "evaporating lotion" for wound care is not original with him He says that a lotion composed of one part of alcohol to ten of water is "much better for our climate than that used in London, composed of one of alcohol to five of water."^[87]

As far as we can determine, we have from Cooper's own hand reference to the use of alcohol only as an ingredient of an "evaporating lotion." As for its rationale we have the implication that he thought use of the lotion would help to control inflammation.

Actually, Cooper had a most sensible approach to wound healing in the pre-antiseptic era. He insisted on adequate incisions for the drainage of infection, including septic joints, with wounds packed open for free drainage until suppuration subsided and clean granulation was established. He had sound surgical instincts. We can surmise that he would have been prompt to accept and apply Listerian principles could he have lived to the day of their dawning.

Treatment of Puerperal Fever

Before leaving the subject of puerperal fever we should further broaden our view of the practice of medicine in America by considering, as an example, the manner in which this devastating disease was being treated during the first half of the 19th century. We have already taken note of the controversies aroused by the views of Holmes and Semmelweis regarding its cause and prevention. With respect to its treatment, however, there appears to have been general agreement. No voice of authority seriously questioned either the benefit or the harm to the patient of the commonly employed regime of blood-letting, purging, mercury and opium. This in spite of the fact that there was no scientific evidence of the effectiveness of any of these remedies.

Blood-letting

Blood-letting as a treatment for many diseases, but especially fevers, dates from antiquity. It was common practice among Greek physicians of the fourth century B.C. some of whom habitually applied it to almost every condition. Blood-letting continued in use as a therapy in the West throughout the Christian era and still had many adherents until near the end of the 19th century. Blood was withdrawn from the general circulation by venesection (phlebotomy), and from local tissues by leeches.^[88]

Venesection

In the mid 1800's prompt and copious blood-letting by venesection was the first and most important treatment in puerperal fever, and was sanctioned by virtually all European and American authors on midwifery. This procedure was perpetuated by the groundless theory that fevers were associated with a harmful accumulation or congestion of blood in the affected part. According to this theory an excess of blood was driven to the inflamed area by an overactive circulatory system and was highly detrimental.

In 1840 Professor Blundell of Guy's Hospital in London, an international authority on obstetrics, recommended repeated venesections in puerperal fever to remove 1200 to 1500 ml. of blood, on the average, and insisted that it should be removed within the first 24 hours for optimum effect. He stated that as much as 1800 ml. or more had sometimes been removed in anomalous cases "with apparent benefit." By way of caution, he advised against bleeding if the patient had already begun to "collapse."^[89]

In 1842 Professor Meigs of Philadelphia graphically described what he believed to be the compelling reason for urgent venesection in puerperal fever:^[90]

To illustrate Professor Meigs's actual practice with respect to venesection, we can quote his comment on one of his own patients:^[91]

As Professor of Obstetrics at Jefferson Medical College, one of the largest and most prestigious American medical schools at the time, the influence of Dr. Meigs on the management of complications of pregnancy was enormous. As a brilliant and dramatic lecturer to hundreds of medical students, as well as a prolific writer, his denial of contagion in puerperal fever and his sanction of copious blood-letting in its therapy carried great authority, and resulted in corresponding ill effects on the practice of midwifery and the well-being of patients.

Leeches

Blood-letting by leeches was recommended by many experts on puerperal fever as an optional adjunct to venesection. According to Professor Wood of the University of Pennsylvania, whose Treatise on the Practice of Medicine was published in 1847 and contained a section on puerperal fever and peritonitis, leeches should be placed on the abdomen immediately after venesection. For example, after one or two large bleedings, from 50 to 150 American leeches should be applied at once in the areas of greatest pain and tenderness, the procedure to be repeated if indicated by persisting symptoms. Professor Meigs had these words of approval for the practice: "While I profess in the strongest terms to confide in the lancet as the first and chief remedy, I would not pretermit any mention of leeches, which, as a secondary and subservient prescription, will be found of the greatest utility in the management of the cases."^[92][93]

Leeches are efficient and painless blood-letters and capable of removing many ounces of blood because they inject an anticoagulant into the tissues where they bite. The application of leeches to the abdominal wall was based on the notion that their proximity to the inflamed pelvis would enable them to "decongest" that region more directly of its excess blood. Leeches had several disadvantages. They were loathsome to the patient and on rare occasion their bites could be lethal by continuing to bleed after removal of the leeches, resulting in exsanguination of the patient. There were reports of patients who, being left unattended for a period of much-needed rest after removal of leeches and application of an abdominal poultice, were later found dead in bed, lying in a pool of blood.

We shall return to the subject of "leeching" when we discuss the various "medical systems" in vogue during the early 1800's.

Mercury and Purging

Immediately following the first venesection, the second or medicinal phase of treatment of puerperal fever was begun This phase consisted of giving drugs that presumably led to the further "depletion" of the congested circulatory system.^[94]

Calomel (mercurous chloride), a mild laxative, was considered the most important drug in puerperal fever and other inflammatory disorders. It was started after the first venesection and continued in serious cases to the point of toxicity as indicated by salivation. It was thought, erroneously, that mercury had a specific anti-inflammatory effect and that salivation was a sign of depletion.

Purging (by such cathartics as castor oil, sulfate of magnesia, and infusion of senna) was, like calomel, begun early in order to assure complete evacuation and thorough decongestion of the gastrointestinal tract.

Emetics once had a great, but fortunately evanescent, reputation as a treatment for puerperal fever, ipecacuanha being the drug of choice for inducing vomiting. The most distinguished advocate of this agent was Doulcet of France who In 1782 observed that puerperal fever often commenced with vomiting:^[95]

Other medicaments including antimony, arsenic and oil of turpentine were tried as therapy but fortunately never came into common use.

Opium, mercifully, was administered freely for analgesia and sedation and represented the only element of the entire therapeutic regimen with a positively beneficial effect when properly administered.^[96]

In the mid 1800's it was assumed that both puerperal fever and autumnal fever, and many other "inflammatory" conditions as well, were associated with an overstimulated and aroused circulatory system as described by Professor Meigs. Theoretically, this hyperdynamic and congested state could be mitigated by "depletion" of the circulation through a combination of blood-letting, purging and mercury - a so-called antiphlogistic (anti-inflammatory) regime. Accordingly, we find that Drake's therapy for autumnal fever consisted of venesection, purging and calomel, with one noteworthy addition: the sulfate of quinine.^[97]

Quinine is an alkaloid isolated from the bark of a species of the cinchona tree, native to Peru. As early as 1600 the Jesuits in Peru knew of the bark's curative effect on intermittent fever but it was not until the mid 1600's that its remedial properties were "certified" by the Pope's physician in Rome where malaria was rampant and where, by 1650, the Peruvian bark had become a popular remedy. Nevertheless, because effectiveness of the bark in malaria was considerably obscured by its indiscriminate use for all fevers, there was resistance to its use by the generality of physicians who remained committed to bleeding and purging. Thus, for the next 150 years, and until isolation of the bark's active principle, quinine sulfate, by French chemists in 1820 made it available in this more usable form, quinine was slow to gain wide acceptance by the medical profession. Finally, by 1850 quinine was in general use as a remedy for the syndrome we now know as malaria. The specificity of quinine's effect exclusively on malaria made it possible to begin the objective differentiation of malaria from other fevers. Although the emerging recognition of quinine as a specific for malaria tended to undermine the antiphlogistic regime, Drake could not bring himself to abandon the old order. He insisted that bleeding, purging and mercury were essential "preparation" of the patient before administration of quinine sulfate.^[98][99]

It is relevant to our evaluation of Drake's vegeto-animalcular hypothesis of the cause of malaria to point out that the elusive plasmodia of the malarial parasite were not found in the blood of malarial patients until 1880. The discovery was made by Alphonse Laveran (1845-1922), a French military medical officer working in a military hospital in Constantine, Algeria. He suspected that the parasite was probably transmitted by a mosquito, but could not prove it.^[100] Sir Ronald Ross (1857-1932), a British army surgeon working in India, identified plasmodia in the stomach wall of Anopheles mosquitoes which had fed on the blood of malarial patients (1897). He also found that sporozoites of the parasite were concentrated in the mosquito's salivary gland. He concluded that they were injected from there into the blood stream of the human host. For this work, which led to effective methods to control mosquitoes and prevent malaria, he was awarded the Nobel Prize in 1902.^[101] By this time clearing of land, drainage of swamps and improved housing had resulted in the control of mosquitoes and the end of malaria as the scourge of the Northwest.

In retrospect, Drake's hypothesis regarding the etiology of malaria was about as close to the mark as was reached until Pasteur and Koch demonstrated the microbial origin of infectious disease; laid to rest the theories of their atmospheric, constitutional or spontaneous origin; and set off an intensive search for specific agents of infection.

As we have seen, malaria was the commonest infectious disease in the Northwest. It was so widely prevalent and unavoidable that it was tolerated stoically by those who could not move to more healthful locations away from the low or "bottom" lands where it was known to be an almost universal complaint. Although malaria was the major cause of recurrent illness and was not infrequently lethal, especially among the very young, it is important to keep in mind that the principal causes of death in the region in the 1850's were a host of other infectious diseases: infant diarrhea; exanthemata in childhood, particularly scarlet fever; diphtheria; pulmonary tuberculosis; lobar pneumonia; typhoid fever; and bacillary dysentery. These nineteenth century destroyers, now well controlled in developed countries, were then a dreaded menace to every family.

To these endemic afflictions were added the periodic visitations of Asiatic Cholera, the most feared of all diseases in the 19th century. This pestilence followed trade routes across the Atlantic and invaded North America for the first time in June 1832. It was carried from Europe to Quebec and Montreal by Irish immigrants fleeing the cholera epidemic in Ireland. Between June 9 and September 2 there were 2127 deaths from cholera in Quebec City. Between June 10 and July 14 there were 1220 deaths from cholera in Montreal. It appeared within the next few months in the New York, Philadelphia, Maryland, Virginia, Kentucky and the Ohio Valley.

By July 1832 the epidemic had already crossed the Great Lakes from Canada into Northern Illinois where the Black Hawk War was in progress. On July 2 General Winfield Scott was dispatched from Buffalo with troops aboard two lake vessels to put down the Indian uprising. General Scott never engaged Black Hawk who was defeated before his arrival in Northern Illinois. Instead, the General encountered cholera which broke out aboard the vessels, disorganizing his expedition and costing the lives of 500 men.^[102]

The plague returned to Northern Illinois in 1866 and attacked Chicago where there were 1581 cases of cholera in that year with 970 deaths, including that of Professor Daniel Brainard of Rush Medical College. Brainard died within less than 24 hours from the onset of the disease. Because of its rapid progress and high mortality rate, cholera struck terror wherever it appeared. It was well-known in some cases to begin in the morning with mild gastrointestinal symptoms and copious watery diarrhea and terminate with dehydration, collapse and death by nightfall. Crowded, unwashed populations living amidst filth and pollution with fecally contaminated water and food supplies were seen to be more susceptible to cholera and typhoid than those living under opposite conditions. This observation, even though the nature of the contagion was unknown, stimulated the inception during the first half of the 19th century of the modern public health movement known as "The Great Sanitary Awakening," devoted to sanitary reform throughout the world.^{[103][104][105]}

Finally, as a rough measure of social and medical progress over the past century and a half we see that the death rate in the nation is now half that in the mid 1800's and life expectancy is twice as long:^[106][107]

	Deaths per 1000 Population	Life Expectancy at Birth
Massachusetts	19 (1860)[108]	39 Years (1850)
All USA	9 (1990)	75 Years (1990)

Medical therapies during the first three quarters of the 19th century, and throughout previous medical history as well, were based on one or another theory of the pathophysiology of disease. In the absence of observations based on scientific principles, these theoretical "systems" sought to account for the signs and symptoms of illness and to devise "logical" treatments to counteract them. Whether a treatment was in fact effective was not objectively evaluated. If patients recovered after receiving a treatment, the favorable response was attributed to the treatment - post hoc ergo propter hoc. As a result, the drugs and medical procedures prescribed were, with the exception of a few specifics, either useless or harmful, a circumstance obscured since prehistoric times by the healing power of nature - vis medicatrix naturae. In an address in 1860 to the Massachusetts Medical Society, Oliver Wendell Holmes reviewed the state of the Art and called on his colleagues to forego obnoxious treatments:^[109]

Several of the medical systems in vogue early in the 1800s will be cited as examples of the genre. Professor Wood's recommendation on leeches in puerperal fever calls attention to their use as definitive therapy in the medical system of the Prince of Leeching, François Joseph Victor Broussais (1772-1838). This colorful veteran of the Napoleonic campaigns was chiefly responsible for founding the famous Paris Clinical School. His style was vigorous and dictatorial. Even his civilian medical practice was conducted with military-like discipline. His dogmatic approach was temporarily persuasive and for a time he was the leading medical figure in Paris. The basis for his immense popularity was, in addition to his dynamic personality, the medical system he conceived and zealously propagated. The Broussais Doctrine, which gained a wide but short-lived prominence on the continent and in America, was merely one in a countless succession of theoretical systems proposed during the prescientific era to explain the manifestations of disease. The importance of systems lay in their determining influence, in the absence of basic facts, on the diagnosis and treatment of medical disorders. Groundless in a scientific sense, some systems were nevertheless remarkably durable as illustrated by the humoral doctrine which regarded the body as composed of four liquids or "humors": blood, phlegm, yellow bile and black bile. This often-refined doctrine survived in modified versions from Hippocrates in the fifth century B.C., through Galen in the second century A.D., and until Rudolf Virchow (1821-1902)) finally dealt a death blow to its surviving remnants with publication of his work on Cellular Pathology in 1858.^[110][111]

After 1700 the validity of medical systems was increasingly challenged by the basic and clinical research of investigators who were in the vanguard of modern biomedical science. However, the still-limited scope of scientific information permitted systematists to continue filling the void well into the 19th century with theories such as the Broussais Doctrine. This Doctrine was a modification of the Brunonian theory, derived by John Brown (1735-1788) from the medical system of his teacher, William Cullen (1710-1790) of Edinburgh. Cullen's system assumed that the body is maintained in a normal state of health by "nervous energy". The nervous system, which is the source of this energy, reacts adversely to certain external stimuli and disease is the result. Cullen regarded almost every disease as a manifestation of nervous reaction.

The Brunonian theory claimed that the essential quality of living tissue is "excitability" and that life itself is non-existent except as the resultant of external and internal stimuli. If these exciting forces are withdrawn, death ensues. Health is defined as a moderate state of excitability resulting from a proper balance of stimuli. Disease is caused by an increase or decrease of excitability and falls into two main groups: "sthenic" diseases (asthenia) are associated with increased and "asthenic" diseases (asthenia) with decreased excitability. Treatment is simple - sedatives (e.g., opium) for sthenia and stimulants (e.g., alcohol) for asthenia. This mode of therapy soon gained many passionate adherents, and as many bitter opponents. Advocates and enemies of Brown's system tended to be noisy and combative. In 1802 a two-day riot between Brunonian and non-Brunonian medical students broke out at the University of Göttingen and had finally to be put down by a troop of cavalry.

As for the controversial Brown himself, his favorite remedies and personal adjuvants were, as might be expected, opium and alcohol. Of his lectures, which attracted many students, it is said:

Hopelessly addicted to drink and narcotic, his downward path led, by way of a term in debtors' prison, to death one night in his 53rd year after taking a very large dose of laudanum.^{[112][113][114]}

Broussais simplified matters by claiming that individual diseases do not exist. For the Brunonian concept of stimulation as the agency of disease, he substituted inflammation. Based on clinical experience and extensive post mortem dissections he concluded that most diseases are merely the physiological expression of inflammation, usually localized in the gastrointestinal tract. For example, fevers in general are a symptom of gastroenteritis. He denied the Hippocratic doctrine of the healing power of nature and therefore thought it necessary to abort disease aggressively by active measures. His standard treatment (the rationale for which is incomprehensible in the present day) was to combat the underlying inflammation by antiphlogistic or weakening measures consisting of a very limited diet plus blood-letting by application of leeches all over the patient's body. From 10 to 50 leeches would be applied at a time. In the year 1833 alone, when Broussais was at the height of his fame, over 40 million leeches were imported into France. Yet eight years earlier, two or three million met all demands.^[115][116]

It was also in 1833 that Oliver Wendell Holmes arrived in Paris for two and a half years of study. The first lectures he attended at the Ecole de Médecine were those of Professor Broussais about whom he wrote:^[117][118]

The authority and popularity of Broussais were just then being eroded by younger members of the faculty who set about exposing the absurdity of his doctrine and the dangerous consequences of treatment by starvation and leeching which reduced some patients to a deplorable state.^[119] Among this new generation of clinicians in Paris was Rene Theophile Hyacinthe Laennec (1781-1826), expert pathologist and the most distinguished internist of his day. He is best remembered as inventor of the stethoscope in 1819, and author of classic treatises on auscultation and percussion. He had a low regard for his colleague, Broussais, to whom he referred in sarcastic terms.

However, it was Laennec's pupil, Pierre Charles Alexandre Louis (1787-1872), founder of medical statistics, who undermined Broussais's arbitrary system in 1835 when he published a memoir entitled Investigations on the Effects of Blood-letting in Some Inflammatory Disorders.^[120] Here for the first time the effectiveness of the age-old practice of venesection was submitted to scientific evaluation. Louis's research consisted of a retrospective study of the response to blood-letting in two series of cases, one of pneumonia and the other of erysipelas of the face. He tabulated and analyzed the data according to his new "Numerical Method" which he described in detail.^[121] By simple arithmetical calculations he compared the carefully observed outcome in untreated patients with similar patients who received treatment. The results showed that blood-letting was not of value in these cases. In the process, he demonstrated the need for rigorous evaluation of the theories and conventional wisdom of clinical medicine. Louis's Numerical Method served to establish the cardinal principle that "the edifice of medicine reposes entirely upon facts, and that truth cannot be elicited but from those which have been well and completely observed".^[122] Medical systems could not withstand such a test and Louis's method of statistical analysis of objective data was now used to discredit them. By mid century systems were being labeled "quackery" and vigorously attacked by the enlightened elements of the profession.^[123]

During the second quarter of the 19th century the hospitals and medical schools of Paris were the preferred destination of American students seeking advanced training abroad. Many future leaders in American medicine were inspired by the progressive spirit of French medicine. Louis, particularly, was respected for his devotion to science and his personal interest in American students, many of whom strengthened the faculties of American schools when they returned home. Holmes, for one, greatly admired Louis and after a few months' attendance at his rounds and lectures reported that "I have learned at least three principles since I have been in Paris; not to take authority when I can have facts; not to guess when I can know; not to think a man must take physic because he is sick."^[124] In 1908 Osler recalled the contribution of the European schools to the development of American medicine and the changes that occurred in their appeal to American students:^[125]

Ether

The discovery of the anesthetic property of ether was one of the most significant medical contributions in the first half of the 19th century. Ether anesthesia was first publicly demonstrated at the Massachusetts General Hospital in Boston on 16 October 1846. William T. G. Morton (1819-1869), a dentist, administered ether vapor (whose properties he had investigated), while Professor John Collins Warren (1778-1866), Harvard surgeon, painlessly ligated a cavernous hemangioma in the left side of the neck of Gilbert Abbott, age 20. Upon successful completion of the operation on the anesthetized patient, Dr. Warren turned to those present and said: "Gentlemen, this is no humbug."^[126]

Dr. Warren published a report of the operation in the Boston Medical and Surgical Journal on 9 December 1846. The endorsement of ether by the highly respected Warren and his surgical colleagues at the MGH led to its immediate acceptance as an anesthetic agent on both sides of the Atlantic. Within a few months medical journals were filled with reports of operations performed under ether anesthesia.^[127]

At the time of the demonstration at the MGH, Dr. Oliver Wendell Holmes was in medical practice in Boston. About a month after the operation he wrote to Dr. Morton with a suggestion on terminology:^[128]

There is no evidence that other advice was sought and the words suggested by Dr. Holmes were readily accepted by the profession and the public. In due course the spelling was simplified to "anesthesia" and anesthetic.

Chloroform

James Young Simpson (1811-1870), Professor of Obstetrics at Edinburgh, first used ether for delivery in January 1847 but, being dissatisfied with its unpleasant odor and tendency to irritate the bronchi, set about looking for a more agreeable anesthetic. At the suggestion of David Waldie, a chemist at Liverpool, he and his assistants tested chloroform by inhaling it themselves in November 1847. Finding it highly effective and bland, they immediately began using it to provide analgesia in childbirth. Later that month he reported his experience to the Medico-Surgical Society of Edinburgh and then proceeded to wage a campaign on behalf of the use of chloroform analgesia to relieve the pangs of childbirth.^[129] The Scottish Calvinist clergy objected on the basis of God's malediction to mothers in Genesis iii, 16 that "in sorrow shalt thou bring forth children; and thy desire shall be to thy husband, and he shall rule over thee," which he countered with the revelation in Genesis ii, 21 that God was the first anesthetist when he "caused a deep sleep to fall upon Adam, and he slept: and he took one of his ribs, and closed up the flesh instead thereof." When Simpson delivered Queen Victoria of her eighth child with the benefit of chloroform in 1853, the ecclesiastics were silenced and he was knighted, to be known thereafter as Sir James Young Simpson, Bart.^[130][131]

In a letter to Professor Meigs at Jefferson Medical College in January 1848, Simpson, eager to encourage the use of chloroform in America, informed him that:^[132]

To which Meigs with his usual self-assurance replied in February:

Once again, as he did with respect to contagion and blood-letting in puerperal fever, Professor Meigs came down on the wrong side of a significant medical issue of his day. He continued to be markedly antagonistic to the use of either chloroform or ether in childbirth and late in the 1840's arranged to demonstrate the danger of anesthesia to his students at Jefferson Medical College. S. Weir Mitchell (1829-1914), later to become the leading American neurologist, was a member of the class and made this note in his diary:^[133]

According to Professor Hodge of the University of Pennsylvania, Meigs continued 15 years later to protest against anesthesia in labor and predicted that, in the course of a few years, it would be banished from practice, except in a few extraordinary cases.^[134]

Here we conclude our survey of the status of medicine and medical care from 1800-1850. We shall look ahead now to the three immortals of science whose contributions during the next half-century most clearly mark the transition to the modern era.

The Germ Theory

In 1854 Pasteur, then 32 years of age, was appointed Professor of Chemistry and Dean of the newly organized Faculté des Sciences in the city of Lille, the richest center of industrial activity in the north of France. When extolling the marvelous discoveries of modern science in his opening speech to the students on 7 December, the young Dean reminded them that "chance only favours the mind which is prepared."^[135] These words, that have echoed ever since through the halls of academe, are a key to Pasteur's own achievements. His experiments were always carefully planned and decisive, but it was his genius to make serendipitous observations of historic significance while solving practical problems - such as the problem brought to him by a certain Monsieur Bigo, the father of one of his students.

In the summer of 1856 M. Bigo came to consult Pasteur concerning the difficulty he was having with the alcoholic fermentation of beet sugar in his distillery. Something was going wrong with the process and the alcohol was turning sour. Pasteur was at first hesitant to undertake a project outside his school. Fortunately for posterity he decided to go to Mr. Bigo's distillery and have a look at his vats. He found that, part of the time and for no apparent reason, the alcoholic fermentation process for which yeast was the ferment began to produce lactic acid, an acid usually obtained from sour milk. Pasteur decided that there were in fact two kinds of fermentation, each independent of the other, going on in M. Bigo's vats: alcoholic fermentation due to yeast and lactic acid fermentation due to the lactic acid bacillus. When the alcoholic fermentation turned sour it was due to the production of lactic acid by a contaminant, the lactic acid bacillus. Pasteur discovered and isolated the bacillus, and believed that the air was the source of the contamination.

Hitherto, fermentation had been described in all the textbooks as a chemical process, but Pasteur had now shown it to be caused, in the case of lactic acid fermentation, by a living organism. Skeptical also of the chemical theory of alcoholic fermentation, he went on to disprove the theory by demonstrating that yeast is the living agent of the process. He reported his findings in a "Mémoire sur la fermentation appelée lactique" (Memoir on the fermentation of lactic acid) in 1857, and a "Mémoire sur la fermentation alcoholique" (Memoir on the fermentation of alcohol) in 1860. Pasteur's experiments proved conclusively that fermentation is caused by microorganisms. In so doing, he provided a biological explanation for a phenomenon generally accepted as a chemical reaction. Furthermore, he established that specific microorganisms are responsible for specific biological processes and, by inference, that specific germs may be the agents of specific diseases. While Pasteur thus laid the foundation for the germ theory of disease, validation of the theory awaited the test of clinical application soon to be undertaken by the British surgeon, Joseph Lister.^[136]

Doctrine of Spontaneous Generation

Pasteur knew that his concept of biological activity by microorganisms was incompatible with the doctrine of spontaneous generation that still had many adherents. In his day the belief persisted that microscopic life forms could be spontaneously generated in putrefying organic material. According to this theory, the microorganisms associated with fermentation were the product and not the cause of the process.

The ancient and hardy doctrine of spontaneous generation, rooted in the speculations of the Greek philosopher Aristotle of the fourth century B.C., was strongly supported by Félix Archimède Pouchet (1800-1872), Director of the Museum of Natural History in Rouen, a French city northeast of Paris. In a paper read before the Paris Academy of Sciences in 1858 he claimed to be able to produce spontaneous generation at will in a sterile culture medium. Pasteur, unerring in his sense that this stubborn doctrine required the coup de grace as only he could administer it, was unwilling to let Pouchet's claim go unchallenged. Therefore, he began an extensive series of meticulous experiments in 1859, the year of Darwin's publication of the Origin of Species - and the year that saw the opening of the first medical school on the Pacific Coast by Elias Cooper. Pasteur's experiments took him from the crowded streets of Paris to the Alps, gathering samples of air in glass flasks containing sterile culture medium. There was rigorous attention to every detail. Flasks opened in the Paris streets grew organisms abundantly, those opened in the high mountains remained sterile with rare exception. To his own satisfaction, and that of the l'Académie des Sciences, Pasteur demonstrated that microorganisms appeared in flasks of sterile culture medium only when contaminated by exposure to contaminated air from the outside, and never by "spontaneous generation." In 1861 he summarized his findings in the essay Sur les corpuscules organisés qui existent dans l'atmosphère. Examen de la doctrine des générations spontanées. (On the organized bodies which exist in the air. Examination of the doctrine of spontaneous generation.)^[137][138]

Pasteur considered the matter closed. Nevertheless, the dispute dragged on and we can detect his exasperation in the tone of his lecture at the Sorbonne in 1864 when he outlined the history of the controversy and concluded by saying:^[139]

Meanwhile, Pouchet continued to generate life in his "sterile" cultures. As a result, doubts of Pasteur's thesis lingered until 1876. By this time Pasteur and his associate, C. Chamberland, had discovered that some bacteria have a resting spore stage during which they are resistant to the temperatures then used in sterilizing experimental cultures. They showed that, in the experiments of Pouchet, the presence of resistant spores in their hay infusion cultures accounted for the subsequent growth. By heating these cultures to 115-120 degrees centigrade, Chamberland destroyed the spores and sterility could be universally maintained in the infusions so treated. The age-old doctrine of spontaneous generation was finally demolished.

Pasteur's seminal contributions are by no means limited to germ theory and spontaneous generation. His other memorable works include the following and many more: identification of the microorganisms responsible for contamination of wine (1863) and for diseases of silkworms (1865); identification of the bacteria causing gas gangrene (Clostridium septicum), furunculosis (Staphylococcus) and puerperal fever (Streptococcus). He showed that the spoiling of wine by living microorganisms could be prevented by heating for about 30 minutes at 68 degrees C. (154.4 degrees F.), a process now known as pasteurization and widely used in the preservation of milk and other liquids. His last and one of his greatest works was on rabies and vaccination for the prevention of rabies and other conditions. These investigations led to the discovery of the principles of acquired immunity and practical methods of producing it by artificial means.^[140]

The British surgeon, Joseph Lister, was the first to demonstrate the medical significance of Pasteur's work on fermentation and spontaneous generation. Pasteur demonstrated by his experiments that living germs are widely distributed in the air and are the agency of fermentation and putrefaction. When Lister read Pasteur's papers in the early 1860's, he concluded that the inflammation, "laudable pus" and "putrid intoxication" which commonly followed open wounds, was caused by microbes from the air and surrounding surfaces.

Lister was well suited for the task of evaluating this new conception of the origin of wound infection, the dreaded nemesis of surgeons. He was born at Upton in the county of Essex of Quaker parents who engendered in him the creed of devotion to the good of mankind, with kindness and consideration for others.^[141] His father, a wine merchant, devoted his leisure to optics and made important contributions to modern microscopy through improvements in achromatic lenses. Exposure to microscopy under his father's tutelage was an early preparation for the important research in microbiology he conducted in later life. The young Lister graduated in Medicine at the University of London in 1852, and in 1854 went up to Edinburgh to study surgery with the distinguished James Syme, whose daughter he married. In 1860, on Syme's recommendation, Lister competed successfully for the chair of surgery at Glasgow, a post he held until 1869. He then returned to Edinburgh where he succeeded Syme and remained until, in 1877, he accepted the position of Professor of Clinical Surgery at King's College, London. There he stayed until his retirement, replete with honors, in 1892.^[142] In 1897, Lord Lister became the first medical man to be elevated to the peerage.^[143]

It was during his tenure as Professor of Surgery at Glasgow from 1860 to 1869 that Lister developed and put to trial the principles of "antiseptic surgery" based on the theory that wound infection could be prevented by destroying with an antiseptic the bacteria in the air, on the skin and other surfaces, and in the wound. After evaluation of various bactericidal agents he chose carbolic acid as most effective for this purpose, including its use as a spray before each operation to kill the microbes in the air. (In 1890 he discontinued the spray, having concluded that it was not an essential.)^[144] The initial procedures devised by Lister were cumbersome and the carbolic acid was irritating to the patient's skin and wound and to medical personnel. He gradually succeeded in minimizing these drawbacks by diluting the carbolic acid and experimenting with various types of antiseptic dressing. By 1865 he was prepared to treat patients, beginning with such cases as compound fractures and chronic (tubercular) abscesses, then moving on to amputations.^[145]

Two years later Lister's first paper on the antiseptic method, published in the Lancet in early 1867, dealt with trials of the method in patients with compound fractures, and included a preliminary report on its prevention of secondary infection when draining tubercular abscesses.^[146] The results fulfilled his "most sanguine anticipations." In reality, the results could not have been more striking, for the patients suffered neither from inflammation and abscess in the wound nor from general sepsis, complications expected to occur frequently in such cases. In the introductory section of the paper, he graciously acknowledged his debt to Pasteur:^[147]

His second paper on the antiseptic method appeared in both the British Medical Journal and the Lancet for 21 September 1867. In this article, entitled "On the Antiseptic Principle in the Practice of Surgery", he discussed the rationale for and technical details of the method, and concluded with the following description of its "salubrious" effect on the hospital environment.^[148][149]

It was thus, with characteristic understatement, that Lister ushered in a new era in the prevention and control of surgical infection - and, by inference, indicted microorganisms as agents of other types of infection.

Lister's first paper on the antiseptic method referred to above reported a series of 10 patients with compound fractures who fared much better under the antiseptic treatment than might have been expected under the usual care. However, more than such "anecdotal" information was needed to convince the sceptics among his surgical colleagues, of whom there were many. By 1870 Lister, who left Glasgow in 1869 to become Professor of Surgery at Edinburgh, had marshaled the evidence his thesis needed for its wider acceptance. In a paper in the Lancet "On the Effects of the Antiseptic System of Treatment upon the Salubrity of a Surgical Hospital", he analyzed the outcome of amputations at Glasgow Infirmary before and after adoption of the antiseptic system. In 1864 and 1866, before adoption of the system, there were 35 amputations with 16 deaths for a mortality rate of 46%. in 1867, '68 and '69, after adoption of the system, there were 40 amputations with 6 deaths for a mortality rate of 15 %.^[150] This was a spectacular improvement in the mortality rate from amputation over that reported from leading British hospitals at the time.^[151]

For over a decade many leading British surgeons failed to recognize the merit of the antiseptic system, and much acrimonious criticism was directed at Lister and his method. When he visited the United States in 1876 to deliver an address at the International Medical Congress in Philadelphia, he was not received with any enthusiasm. The Americans were slow to accept Listerism, and as late as the meeting of the American Surgical Association in 1882, the Lancet reported that "Anti-Listerians were in the majority; . . . they relied for support upon the statements of others. . . . Surely it is too late in the day (for them) to contest the truth of the germ theory."^[152] Levi Cooper Lane, who began his surgical career prior to Listerism, never fully accommodated to the restrictions imposed by the antiseptic and aseptic methods and gave as the reason: "You can't teach an old dog new tricks."^[153]

However, in Britain and on the continent, the antiseptic method had by 1879 been widely applied, and Lister's findings amply confirmed. In that year Lister attended the International Congress of Medical Science at Amsterdam where his reception was far different from that he received from the Americans. When he rose to deliver his address, he was greeted by an overwhelming ovation that only abated when the President of the Congress came forward to take his hand and say:^[154]

Lister's work was the first convincing application of the germ theory to the control of human disease, and as such it spurred great progress in surgery and other fields. "There is no instance in the history of surgery, and indeed few in the history of science, in which a deduction has been so completely verified when put to the test."^[155]

It soon became apparent that it would be more efficient to prevent wound contamination by sterilizing in advance all the drapes, dressings, gowns and instruments coming into contact with the operative field - thus creating an "aseptic" environment for the wound. This became feasible when Ernst von Bergmann (1836-1907), Professor of Surgery at Berlin, introduced steam sterilization in 1886 and inaugurated the present "aseptic" method in 1891. The procedures of aseptic surgery have now evolved over the past century to an elaborate standardized routine, including face masks, rubber gloves and laminar air flow; and, instead of carbolic acid, employing a broad spectrum of less noxious bactericidal antiseptics. The current regime, a combination of aseptic and antiseptic technology, is highly effective in barring live microorganisms from the wound - which is, in essence, the goal defined originally by Lister in 1867.^[156][157]

With the contributions of Lister, three essential pillars of modern surgery - anatomy, anesthesia and antisepsis/asepsis - were now in place. When the risk of surgical infection was reduced to a minimum by application of the Listerian principle, the domain of surgery expanded immediately to include bones and joints, body cavities, and vascular and other systems, a progression that continues to this day.

Robert Koch, native of Hannover, Germany, was the co-founder with Pasteur of the new field of bacteriology. Whereas Pasteur was a chemist who became a microbiologist and immunologist, Koch was a practicing physician who became the world's preeminent bacteriologist and investigator of infectious diseases. Following a medical degree in Göttingen in 1866 and service in the Franco-Prussian War, Koch was appointed district physician at Woolskin where he combined his country practice with microscopic studies.

He began by working out the complete life-history and sporulation of the anthrax bacillus, and proving it to be the cause of the disease. When he demonstrated his culture methods and results to a group of well-known scientists at the Breslau Botanical Institute in 1876, they declared his discovery to be the greatest yet made in bacteriology.

Koch's many other remarkable contributions to the creation of a new science included identification of the specific microbial agents responsible for two of humanity's greatest plagues: the tubercle bacillus in 1882 and the cholera vibrio in 1883. His paper on the tubercle bacillus contains the first statement of the steps necessary to establish the pathogenic nature of a given microorganism, steps now known as "Koch's postulates." His elegant techniques of staining and culturing, and his historic discovery of two of the world's most dangerous pathogens, coupled with his other wide-ranging scientific efforts, settled with finality the question of the microbiologic origin of infectious disease and earned for him the Nobel Prize in 1905.^[158][159]

By verifying the germ theory , the work of Pasteur, Lister and Koch ushered in the Golden Era of Microbiology which began with a phenomenal surge in research activity that shows no sign of abating to the present day. The search for causative organisms of specific diseases dominated the three decades from 1870 to 1900 and was highly successful. More than 20 pathogenic bacteria causing specific human diseases were identified, including:^[160][161]

Date	Disease	Organism	Discoverer
1868	Leprosy	Mycobacterium leprae	Hansen
1878	Furuncule (Boil)	Staphylococcus	Pasteur
1879	Puerperal Fever	Streptococcus	Pasteur
1879	Gonorrhea	Gonococcus	Neisser
1880	Typhoid Fever	Salmonella typhi	Eberth
1882	Tuberculosis	Mycobacterium tuberculosis	Koch
1883	Cholera	Vibrio cholera	Koch
1883	Diphtheria	Corynebacterium diphtheriae	Klebs
1884	Tetanus	Clostridium tetani	Nicolaier
1886	Pneumonia	Pneumococcus	Fraenkel
1887	Meningitis	Meningococcus	Weichselbaum
1892	Gas Gangrene	Clostridium welchii	Welch
1894	Bubonic Plague	Pasturella pestis	Kitasato
1898	Dysentery	Shigella shigae	Shiga

The predecessors to Stanford Medical School - Medical Department of the University of the Pacific, Medical College of the Pacific and Cooper Medical College - all evolved between 1850 and 1900. Medicine made more progress during this period than during any previous half century in the history of the world. In later chapters we shall see how these predecessor schools responded to the remarkable changes in medicine and medical education then in progress, and how they acquired the resources and programs that assured a smooth transition to Stanford auspices in 1908.

1. Samuel E. Morison , The Oxford History of the American People (New York: Oxford University Press, 1965), p. 50.
2. Samuel E. Morison , The Oxford History of the American People (New York: Oxford University Press, 1965), p. 56.
3. David J. Davis , ed., History of Medical Practice in Illinois, vol. 2 , 1850-1900 (Chicago: Lakeside Press, 1955), pp. 26-35 Lane Library catalog record
4. Norman D. Levine, comp., A Selection from Malaria in the Interior Valley of North America by Daniel Drake (Urbana: University of Illinois Press, 1964), p. xviii Lane Library catalog record
5. Erwin H. Ackerknecht , "Malaria in the Upper Mississippi Valley, 1760-1900," Bulletin of History of Medicine, Supplement No 4 (1945), p.23 Lane Library catalog record
6. Erwin H. Ackerknecht , "Malaria in the Upper Mississippi Valley, 1760-1900," Bulletin of History of Medicine, Supplement No 4 (1945), p. 24 Lane Library catalog record
7. William N. Bispham , Malaria: Its Diagnosis, Treatment and Prophylaxis (Baltimore: Williams and Wilkins, 1944), pp. 59-82 Lane Library catalog record
8. H. M. Gilles , Management of Severe and Complicated Malaria: A Practical Handbook (Geneva: World Health Organization, 1991), 56 pp Lane Library catalog record
9. Erwin H. Ackerknecht , "Malaria in the Upper Mississippi Valley, 1760-1900," Bulletin of History of Medicine, Supplement No 4 (1945), p.1 Lane Library catalog record
10. William N. Bispham , Malaria: Its Diagnosis, Treatment and Prophylaxis (Baltimore: Williams and Wilkins, 1944), pp. 1-7 Lane Library catalog record
11. M. L. Duran-Reynals , The Fever Park Tree: The Pageant of Quinine (Garden City, New York: Doubleday, 1946), pp. 1-4.
12. H. M. Gilles , Management of Severe and Complicated Malaria: A Practical Handbook (Geneva: World Health Organization, 1991), p. v. Lane Library catalog record
13. David J. Davis , ed., History of Medical Practice in Illinois, vol. 2 , 1850-1900 (Chicago: Lakeside Press, 1955), p. 19 Lane Library catalog record
14. Erwin H. Ackerknecht , "Malaria in the Upper Mississippi Valley, 1760-1900," Bulletin of History of Medicine, Supplement No 4 (1945), pp. 29-31 Lane Library catalog record
15. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), 878 pp Lane Library catalog record
16. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), p. 703 Lane Library catalog record
17. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), pp. 716-718 Lane Library catalog record
18. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), pp. 719-723 Lane Library catalog record
19. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), pp. 723-728 Lane Library catalog record
20. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), pp. 727-728 Lane Library catalog record
21. Erwin H. Ackerknecht , A Short History of Medicine (New York: Ronald Press, 1955), pp. 144-156 Lane Library catalog record
22. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 310-406 Lane Library catalog record
23. Charles-Edward A. Winslow , The Conquest of Epidemic Disease (Princeton University Press, 1943), pp. 117-143 Lane Library catalog record
24. Charles-Edward A. Winslow , Man and Epidemics (Princeton: Princeton University Press, 1952), pp. 200-208 Lane Library catalog record
25. Charles-Edward A. Winslow , Man and Epidemics (Princeton: Princeton University Press, 1952), pp. 144-153. Lane Library catalog record
26. Charles-Edward A. Winslow , Man and Epidemics (Princeton: Princeton University Press, 1952), pp. 153-154 Lane Library catalog record
27. Charles-Edward A. Winslow , Man and Epidemics (Princeton: Princeton University Press, 1952), pp. 154-160 Lane Library catalog record
28. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843): 503-530, as reprinted in Medical Classics 1, no. 3 (Nov 1936): 211-243 Lane Library catalog record
29. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843), as reprinted in Medical Classics 1, no. 3 (Nov 1936): p. 213 Lane Library catalog record
30. Alexander Gordon , "A Treatise on the Epidemic Puerperal Fever of Aberdeen" . Published in 1795 and reprinted in Charles D. Meigs, compiler, The History, Pathology, and Treatment of Puerperal Fever and Crural Phlebitis (Philadelphia: Ed Barrington and Geo. D. Haswell, 1842), p. 31 and pp. 50-51. The parenthetical interpolations in the last two paragraphs of this excerpt from Gordon's Treatise are the words of Oliver Wendell Holmes who quotes the passage on page 216 of his article on "The contagiousness of puerperal fever."
31. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843), as reprinted in Medical Classics 1, no. 3 (Nov 1936): p. 240 Lane Library catalog record
32. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843), as reprinted in Medical Classics 1, no. 3 (Nov 1936): pp. 219-220 Lane Library catalog record
33. James Blundell , The Principles and Practice of Obstetricy, ed. Thomas Castle (London: E. Cox, St. Thomas Street, Southwark, 1840), pp. 765-767 Lane Library catalog record
34. "Puerperal Fever," Transactions of the College of Physicians of Philadelphia Quarterly Summary (May, June and July), Meeting for 3 May 1842, pp. 50-61.
35. Charles D. Meigs , letter to the editor, Medical Examiner and Retrospect of the Medical Sciences 6, no. 1 (Jan 21, 1843): 3 Lane Library catalog record
36. Charles D. Meigs, compiler, Treatment of Puerperal Fever and Crural Phlebitis (Philadelphia: Ed. Barrington and Geo. D. Haswell, 1842), p. 338.
37. Oliver Wendell Holmes , "Puerperal Fever as a Private Pestilence" (Boston: Ticknor and Fields, 1855), as reprinted in Medical Classics 1, no. 3 (Nov 1936): 252 Lane Library catalog record
38. Oliver Wendell Holmes , "Puerperal Fever as a Private Pestilence" (Boston: Ticknor and Fields, 1855), as reprinted in Medical Classics 1, no. 3 (Nov 1936): 246 Lane Library catalog record
39. Charles D. Meigs , The Philadelphia Practice of Midwifery (Philadelphia: James Kay, Jun., and Brother, 1842), 408 pp Lane Library catalog record
40. Oliver Wendell Holmes , "Puerperal Fever as a Private Pestilence" (Boston: Ticknor and Fields, 1855), as reprinted in Medical Classics 1, no. 3 (Nov 1936): 246 Lane Library catalog record
41. William Osler , "Oliver Wendell Holmes" in An Alabama Student and Other Biographical Essays (New York: Henry Frowde, 1908), p. 66 Lane Library catalog record
42. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843), as reprinted in Medical Classics 1, no. 3 (Nov 1936): pp. 237-238 Lane Library catalog record
43. Edward Rigby , A System of Midwifery (Philadelphia: Lea and Blanchard, 1841), p. 458 Lane Library catalog record
44. Alexander Gordon , "A Treatise on the Epidemic Puerperal Fever of Aberdeen" . Published in 1795 and reprinted in Charles D. Meigs, compiler, The History, Pathology, and Treatment of Puerperal Fever and Crural Phlebitis (Philadelphia: Ed Barrington and Geo. D. Haswell, 1842), p. 62.
45. William Hey , "A Treatise on the Puerperal Fever: Illustrated by Cases which occurred in Leeds and its Vicinity, in the years 1809-1812." Published in 1817 and reprinted in Meigs , Treatment of Puerperal Fever and Crural Phlebitis, p. 150 Lane Library catalog record
46. John Armstrong , "Facts and Observations Relative to the Fever Commonly Called Puerperal." Published previously and reprinted in Meigs, Treatment of Puerperal Fever and Crural Phlebitis, p 179 Lane Library catalog record
47. Robert Lee , "On Puerperal Fever and Crural Phlebitis" , Published previously and reprinted in Meigs, Treatment of Puerperal Fever and Crural Phlebitis, p. 279.
48. Edward Rigby , A System of Midwifery (Philadelphia: Lea and Blanchard, 1841), p. 458 Lane Library catalog record
49. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843), as reprinted in Medical Classics 1, no. 3 (Nov 1936): pp. 242-243 Lane Library catalog record
50. James Copland , A Dictionary of Practical Medicine. vol. 7, ed. Charles A. Lee (New York: Harper and Brothers, 1852), s.v. "Puerperal Fevers", p. 559 Lane Library catalog record
51. Oliver Wendell Holmes , "Puerperal Fever as a Private Pestilence" (Boston: Ticknor and Fields, 1855), as reprinted in Medical Classics 1, no. 3 (Nov 1936): pp. 245-268 Lane Library catalog record
52. Thomas F. Harrington , The Harvard Medical School: A History, Narrative and Documentary, 1782- 1905, vol. 2 (New York: Lewis Publishing Co., 1905), pp. 769-799 Lane Library catalog record
53. J. H. Mason Knox , Jr. , "The medical life of Oliver Wendell Holmes," Johns Hopkins Hospital Bulletin 18, no. 191 (Feb 1907): 45-51 Lane Library catalog record
54. William Osler , "Oliver Wendell Holmes" in An Alabama Student and Other Biographical Essays (New York: Henry Frowde, 1908), pp. 55-67 Lane Library catalog record
55. Walter F. Taylor , The Story of American Letters (Chicago: Henry Regnery Co., 1956), pp. 189-193.
56. Oliver Wendell Holmes , "Puerperal Fever as a Private Pestilence" (Boston: Ticknor and Fields, 1855), as reprinted in Medical Classics 1, no. 3 (Nov 1936): pp. 264-65 RLane Library catalog record
57. F. H. von Arnath , "Note sur le Moyen Proposé et Employe par M. Semmeliveis pour Empécher le Développment des ´Epidémies Puerpérales dans L'Hospice de la Maternité de Vienne," Annales D'Hygiène Publique et de Médicine Légale Tome 45, 2 Partie (Janvier 1851): 281-90.
58. C. H. F. Routh , "On the causes of the endemic puerperal fever of Vienna," Proceedings of the Royal Me.-Chirurg. Soc., 28 November 1848, as reviewed in American J. Medical Sciences 17 (Apr 1849): 509-510.
59. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 7-17 Lane Library catalog record
60. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), p. 86 Lane Library catalog record
61. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 28-48 Lane Library catalog record
62. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 58-61 Lane Library catalog record
63. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 48-49 Lane Library catalog record
64. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 66-67 Lane Library catalog record
65. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 197-201 Lane Library catalog record
66. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 65-69 Lane Library catalog record
67. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 70-71 Lane Library catalog record
68. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 108-109 Lane Library catalog record
69. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 71-72 Lane Library catalog record
70. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 142-148 Lane Library catalog record
71. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 81-87 and 111-26 Lane Library catalog record
72. Ferdinand von Hebra , "Experience of the highest importance concerning the etiology of epidemic puerperal fever at the Lying-in Hospital," Zeitschrift der k. k. Gesellschaft der Aerzte zu Wien 1847 December, as reprinted in Sinclair, Semmelweis, pp. 64-67 Lane Library catalog record
73. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 83-85 Lane Library catalog record
74. Ignaz P. Semmelweis , The Etiology, Concept, and Prophylaxis of Puerperal Fever (Budapest and Vienna: 1861), 543 pp.
75. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 200-245 Lane Library catalog record
76. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 176-178 Lane Library catalog record
77. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), p. 124 Lane Library catalog record
78. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 152-194 and 245-259. Lane Library catalog record
79. William J. Sinclair , Semmelweis: His Life and Doctrine (Manchester: University Press, 1909), pp. 250-251 Lane Library catalog record
80. Frank G. Slaughter , Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), pp. 193-194 Lane Library catalog record
81. Oliver Wendell Holmes , "The contagiousness of puerperal fever," New England Quarterly Journal of Medicine and Surgery 1 (1843), as reprinted in Medical Classics 1, no. 3 (Nov 1936): pp. 211 Lane Library catalog record
82. Frank G. Slaughter, Immortal Magyar: Semmelweis, Conqueror of Childbed Fever (New York: Harry Schuman, 1950), p. 202 Lane Library catalog record
83. René Vallery-Radot , The Life of Pasteur (Garden City, New York: Doubleday, Doran and Co., 1928), p. 291 Lane Library catalog record
84. Emmet Rixford , "Master Surgeons of America," Surgery, Gynecology and Obstetrics 49, no. 6 (Dec 1929): 864.
85. Emmet Rixford , "Early history of medical education in California," Annals of Surgery 88, no. 3 (Sep 1928): 324 Lane Library catalog record
86. Elias S. Cooper , "Editors' Table: Conservative Surgery in San Francisco," San Francisco Medical Press 2, no. 5 (Jan 1861): 35 Lane Library catalog record
87. Elias S. Cooper , "Abstract of Proceedings of the Fifth Annual Session of the Medical Society of the State of California: Synopsis of Report on Surgery by E. S. Cooper," San Francisco Medical Press 1, no. 2 (Apr 1860): 70-71 Lane Library catalog record
88. Charles Singer and E. Ashworth Underwood , A Short History of Medicine, 2nd ed. (New York: Oxford University Press, 1962), p. 50 Lane Library catalog record
89. James Blundell , The Principles and Practice of Obstetricy, ed. Thomas Castle (London: E. Cox, St. Thomas Street, Southwark, 1840), p. 748 Lane Library catalog record
90. Charles D. Meigs , The Philadelphia Practice of Midwifery (Philadelphia: James Kay, Jun., and Brother, 1842), pp. 370-371 Lane Library catalog record
91. Charles D. Meigs , "Introductory Essay," in Treatment of Puerperal Fever and Crural Phlebitis (Philadelphia: Ed. Barrington and Geo. D. Haswell, 1842), pp. 26-28.
92. George B. Wood , A Treatise on the Practice of Medicine, vol. 1 (Philadelphia: Grigg, Elliot, and Co., 1847), p. 690 Lane Library catalog record
93. Charles D. Meigs , The Philadelphia Practice of Midwifery (Philadelphia: James Kay, Jun., and Brother, 1842), p. 372 Lane Library catalog record
94. George B. Wood , A Treatise on the Practice of Medicine, vol. 1 (Philadelphia: Grigg, Elliot, and Co., 1847), pp. 689-693 Lane Library catalog record
95. James Copland , A Dictionary of Practical Medicine. vol. 7, ed. Charles A. Lee (New York: Harper and Brothers, 1852), s.v. "Puerperal Fevers", p. 591 Lane Library catalog record
96. George B. Wood , A Treatise on the Practice of Medicine, vol. 1 (Philadelphia: Grigg, Elliot, and Co., 1847), p. 690 Lane Library catalog record
97. Daniel Drake , Systematic Treatise, Historical, Etiological, and Practical, on the Principal Diseases of the Interior Valley of North America (Cincinnati: Winthrop B. Smith Co., 1850), pp. 786-794 Lane Library catalog record
98. M. L. Duran-Reynals , The Fever Park Tree: The Pageant of Quinine (Garden City, New York: Doubleday, 1946), pp. 33-64 Lane Library catalog record
99. William N. Bispham , Malaria: Its Diagnosis, Treatment and Prophylaxis (Baltimore: Williams and Wilkins, 1944), pp. 112-114 Lane Library catalog record
100. William N. Bispham , Malaria: Its Diagnosis, Treatment and Prophylaxis (Baltimore: Williams and Wilkins, 1944), pp. 5-6 Lane Library catalog record
101. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 707-708 Lane Library catalog record
102. Geoffrey Marks and William K. Beauty , Epidemics (New York: Charles Scribner's Sons, 1976), pp.199-204 Lane Library catalog record
103. Geoffrey Marks and William K. Beauty , Epidemics (New York: Charles Scribner's Sons, 1976), pp.209-212 Lane Library catalog record
104. David J. Davis , ed., History of Medical Practice in Illinois, vol. 2 , 1850-1900 (Chicago: Lakeside Press, 1955), p. 121 Lane Library catalog record
105. Charles-Edward A. Winslow , The Conquest of Epidemic Disease (Princeton University Press, 1943), pp. 236-266 Lane Library catalog record
106. U.S. Bureau of the Census , Historical Statistics of the United States, Colonial Times to 1970, Bicentennial Edition, Part 1 (Washington, D.C., 1975), Series B 193-200, "Death Rate, for Massachusetts," p. 63; Series B 126-135, "Expectation of Life at Birth for Massachusetts," p. 56 Lane Library catalog record
107. U.S. Bureau of the Census , Statistical Abstract of the United States: 1993, 113th edition (Washington, DC), Table No. 120, "Deaths and Death Rates, by State: 1980-1991," p. 88; Table No. 117, "Expectation of Life at Birth: 1990. All USA," p. 86.
108. These data for the mid 1800's are available only for the state of Massachusetts which are therefore assumed to be representative of the nation as a whole.
109. Oliver Wendell Holmes , "Currents and Counter-Currents in Medical Science," in Medical Essays 1842- 1882 (Boston: Houghton, Mifflin and Co., 1895), p. 202 Lane Library catalog record
110. Charles Singer and E. Ashworth Underwood , A Short History of Medicine, 2nd ed. (New York: Oxford University Press, 1962), p. 40 and p. 46 Lane Library catalog record
111. Douglas Guthrie , A History of Medicine (Philadelphia: Lippincott Co., 1946), p. 76 and pp. 282-283 Lane Library catalog record
112. Erwin H. Ackerknecht , A Short History of Medicine (New York: Ronald Press, 1955), p. 119 Lane Library catalog record
113. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 313-315 Lane Library catalog record
114. Ralph H. Major , A History of Medicine, vol. 2 (Springfield: Charles C. Thomas, 1954), p. 593 Lane Library catalog record
115. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 409-410 Lane Library catalog record
116. Charles Singer and E. Ashworth Underwood , A Short History of Medicine, 2nd ed. (New York: Oxford University Press, 1962), pp. 282-283 Lane Library catalog record
117. Ralph H. Major , A History of Medicine, vol. 2 (Springfield: Charles C. Thomas, 1954), p. 667 Lane Library catalog record
118. Catherine D. Bowen, Yankee from Olympus: Justice Holmes and His Family (Boston: Little, Brown and Co., 1944), pp. 65-67
119. Oliver Wendell Holmes , "Dissertation on Neuralgia," in Boylston Prize Dissertations for the Years 1836 and 1837 (Boston: Charles C. Little and James Brown, 1838), pp. 192-193 Lane Library catalog record
120. Pierre C. A. Louis , Recherches sur les Effets de la Saignée dans Quelques Maladies Inflammatoires (Paris: J.B. Bailliere, Libraire de L'Académie Royale de Médecine, 1835), pp. 33-69.
121. Pierre C. A. Louis , Recherches sur les Effets de la Saignée dans Quelques Maladies Inflammatoires (Paris: J.B. Bailliere, Libraire de L'Académie Royale de Médecine, 1835), pp. 70-117.
122. William Osler , "The Influence of Louis on American Medicine," in An Alabama Student and Other Biographical Essays (New York: Henry Frowde, 1908), p. 193 Lane Library catalog record
123. Oliver Wendell Holmes , "Homoeopathy and its Kindred Delusions," in Medical Essays 1842-1882 (Boston: Houghton, Mifflin and Co., 1895), pp. 1-102 Lane Library catalog record
124. Eleanor M. Tilton, Amiable Autocrat: A Biography of Dr. Oliver Wendell Holmes (New York; Henry Schuman, 1947), pp. 96-105 Lane Library catalog record
125. William Osler, "Oliver Wendell Holmes" in An Alabama Student and Other Biographical Essays (New York: Henry Frowde, 1908), pp. 57-58 Lane Library catalog record
126. Washington Ayres , "The Discovery of Anesthesia by Ether; With an Account of the First Operation Performed under its influence at the Massachusetts General Hospital, and an Extract from the Record Book of the Hospital," Occidental Medical Times 10, no. 3 (Mar 1896): 121-129 Lane Library catalog record
127. John C. Warren , "Inhalation of Ethereal Vapor for the Prevention of Pain in Surgical Operations," Boston Medical and Surgical Journal 34, no. 19 (Dec 1846): 375-379 Lane Library catalog record
128. A.M. H. Armstrong Davison , The Evolution of Anesthesia (Baltimore: The Williams and Wilkind Co., 1965), pp. 17-18 Lane Library catalog record
129. James Y. Simpson, "On a new anaesthetic agent, more efficient than sulfuric ether," Lancet 2, no. 20 (Nov 1847): 549-550 Lane Library catalog record
130. Ralph H. Major, A History of Medicine, vol. 2 (Springfield: Charles C. Thomas, 1954), p. 820 Lane Library catalog record
131. Victor Robinson , Victory over Pain: A History of Anesthesia (New York: Henry Schuman, 1946), p. 204. Lane Library catalog record
132. James Y. Simpson and Charles D. Meigs , "On chloroform," North-Western Medical and Surgical Journal 1, no. 2 (Jun-Jul 1848): 151-158 Lane Library catalog record
133. Anna R. Burr , Weir Mitchell: His Life and Letters (New York: Duffield and Co., 1930), p. 45. Lane Library catalog record
134. James E. Eckenhoff , Anesthesia from Colonial Times: A History of Anesthesia at the University of Pennsylvania (Philadelphia: J.B. Lippincott Co.,1966), p. 27-28 Lane Library catalog record
135. René Vallery-Radot , The Life of Pasteur (Garden City, New York: Doubleday, Doran and Co., 1928), pp. 75-79 Lane Library catalog record
136. Rene J. Dubos , Louis Pasteur: Free Lance of Science (Boston: Little, Brown and Co., 1950), pp. 124-130 Lane Library catalog record
137. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), p. 101 Lane Library catalog record
138. Rene J. Dubos , Louis Pasteur: Free Lance of Science (Boston: Little, Brown and Co., 1950), pp. 165-176. Lane Library catalog record
139. John H. Mann, Louis Pasteur: Founder of Bacteriology (New York: Charles Scribner's Sons, 1964), p. 60 Lane Library catalog record
140. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 375-378 Lane Library catalog record
141. A. Logan Turner, ed., Joseph, Baron Lister: Centenary Volume 1827-1927(London: Oliver and Boyd, 1927), pp. 1-3 Lane Library catalog record
142. A. Logan Turner, ed., Joseph, Baron Lister: Centenary Volume 1827-1927 (London: Oliver and Boyd, 1927), p. 20 Lane Library catalog record
143. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 588-592 Lane Library catalog record
144. G. T. Wrench , Lord Lister: His Life and Work (London: T. Fisher Unwin, 1914), p. 309 Lane Library catalog record
145. Richard A. Leonardo , History of Surgery (New York: Froben Press, 1943), p. 333-337 Lane Library catalog record
146. Joseph Lister , "On a new method of treating compound fractures, abscess, etc. with observations on the conditions of suppuration," Lancet 1 (Mar 16, 1867): 326-329; 1 (Mar 23): 357-359; 1 (Mar 30): 387-389; 1 (Apr 27): 507-509; 2 (Jul 27): 95-96 Lane Library catalog record
147. Joseph Lister, "On a new method of treating compound fractures, abscess, etc. with observations on the conditions of suppuration," Lancet 1 (Mar 16, 1867): 327 Lane Library catalog record
148. Joseph Lister, "On the antiseptic principle in the practice of surgery," British Medical Journal 2 (Sep 21, 1867): 248 Lane Library catalog record
149. Joseph Lister , "On the antiseptic principle in the practice of surgery," Lancet 2 (Sep 21, 1967): 356 Lane Library catalog record
150. Joseph Lister, "On the effects of the antiseptic system of treatment upon the salubrity of a surgical hospital," Lancet 1 (Jan 1, 1870): 4-6; 1 (Jan 8): 40-42 Lane Library catalog record
151. Henry Lamond , letter to the editor, "Professor Lister and the Glasgow Infirmary," Lancet 1 (Jan 29, 1870): 175.
152. G. T. Wrench, Lord Lister: His Life and Work (London: T. Fisher Unwin, 1914), pp. 263-264 Lane Library catalog record
153. Emmet Rixford, "Then and Now - Personal Recollections,"Western Journal of Surgery, Obstetrics and Gynecology 41, no. 7 (Jul 1933): 376 Lane Library catalog record
154. G. T. Wrench , Lord Lister: His Life and Work (London: T. Fisher Unwin, 1914), p. 287 Lane Library catalog record
155. Joseph Lister , The Collected Papers of Joseph, Baron Lister, vol. 1 (Oxford: Clarendon Press, 1909), p. xxxi Lane Library catalog record
156. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 594-595 Lane Library catalog record
157. Richard A. Leonardo , History of Surgery (New York: Froben Press, 1943), p. 335 Lane Library catalog record
158. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 578-580 Lane Library catalog record
159. Charles-Edward A. Winslow , The Conquest of Epidemic Disease (Princeton University Press, 1943), pp. 307-310 Lane Library catalog record
160. Fielding H. Garrison , An Introduction to the History of Medicine, 4th ed., reprinted 1960 (Philadelphia: W.B. Saunders, 1929), pp. 576-77 and p. 582 Lane Library catalog record
161. Charles Singer and E. Ashworth Underwood, A Short History of Medicine, 2nd ed. (New York: Oxford University Press, 1962), pp. 390-395 Lane Library catalog record