Richard Noll
email: richard.noll@desales.edu

Frank Billings

Gideon Wells

Keywords: autointoxication theory in psychiatry, Bayard Taylor Holmes, dementia praecox, focal infection theory in psychiatry, surgical treatments in psychiatry

Part I of this article on Bayard Taylor Holmes , a Chicago physician and surgeon, detailed his laboratory research on dementia praecox and his presumed discovery in 1915 of evidence in support of a focal infection theory of its aetiology. In May 1916 he began to experiment with a rational therapy based on this theory: abdominal surgery and daily irrigations of the colon. He operated first on his own son, who had been afflicted with dementia praecox since 1905, but he died four days later. Part II deals with Holmes' continued surgical treatment of dementia praecox patients and the outcomes of the operations. It also describes how Holmes set up the short-lived Psychiatric Research Laboratory of the Psychopathic Hospital at Cook County Hospital in 1917, and discusses the dismissal of a key research colleague, H. M. Jones, whose experimental results directly contradicted those of Holmes.

from Holmes and his work on dementia praecox after April 1916? Perhaps it had something to do with the sudden shift in focus from basic research to radical treatment that followed the signing of the contract for the proposed Cooperative Research Laboratory by the newly emboldened, and temperamentally incautious, Bayard Taylor Holmes.

April 1916: 'I intended to act upon the rational indications without delay'

April 1916 was the high-water mark of the career of Bayard Holmes. He had articulated an autointoxication or focal infection theory of dementia praecox that was congruent with current medical thinking and had conducted primary research that, he believed, provided compelling evidence supporting it. He had received the blessing of the powerful Sprague Institute and was promised financial backing for a complex of laboratories to be devoted solely to work on his discoveries, a dream of his since 1911. 3 And it was in this month that Holmes submitted for publication the paper he regarded as his most significant contribution to science, 'The relation of caecal stasis to dementia praecox'. Holmes underwent a personal transformation in his thinking at this time. The careful laboratory researcher had become impatient, and the physician/healer in Holmes now supplanted the cautious scientist. As he himself later noted when reflecting back on his career, '[this article] was offered for publication in April 1916. The facts it contains seemed to me irrefutable at the time and I intended to act upon the rational indications without delay' (Holmes, 1921a: 137). And so he did. As the months of stalling by the Sprague Institute dragged on, Holmes refused to wait for the opening of the Cooperative Laboratory to conduct further research before trying out experimental treatments: 'It has been forced upon me as a conviction that in a condition so desperate, treatment should be begun even before absolute scientific demonstration of a theory could be reached' (Holmes, 1918c: 48).

Caecostomy or appendicostomy followed by daily irrigations of the caecum would be the new rational treatment of dementia praecox. If the irrigations were performed daily to prevent faecal stasis in the caecum, the toxaemia symptoms of dementia praecox should diminish or disappear entirely. For Holmes, this treatment was rational in two senses. First, it followed logically from his theory of the cause of dementia praecox. And second, it was consistent with contemporary medical practice. Surgical removal of teeth, tonsils, sections of organs or other bodily tissue had long been the only effective treatment available to believers in the focal infection theory of Billings and others, such as the surgeon William Arbuthnot Lane , who believed that colectomies were appropriate to treat constipation and to prevent autointoxication arising from faecal stasis [START_REF] Dally | Fantasy surgery, 1880-1930, with special reference to Sir William Arbuthnot Lane[END_REF]. In Britain, autointoxication due to intestinal stasis is still known as Sir Abuthnot Lane's Disease. As the medical historian Roy Porter (1997: 601) pointed out, focal sepsis was a 'fashionable interwar diagnosis' that led to numerous medical misadventures. But it was literally cutting-edge medical science in 1916. Abdominal surgery had already been conducted on psychiatric patients, primarily women, who suffered the removal of their ovaries or uterus in an attempt to cure neurasthenia or hysteria. Only relatively recently [START_REF] Kraepelin | Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. Fünfte[END_REF], dementia praecox had been described as a diagnostic entity, and there was no body of medical literature on the efficacy of surgical interventions. If dementia praecox was a true physical disease caused by a focal infection in the caecum, it made perfect sense to Holmes -a specialist in abdominal surgery who had written a textbook on the subject in 1904 and who knew and was influenced by the work of the famous Lane -that surgical intervention was a rational response. Like many surgeons, Holmes had an almost fetishistic fascination with one specific bodily structure, in his case the appendix, which he considered 'the most mournfully interesting and unique structure in the body' (Holmes, 1904: xv).

In May 1916 Holmes proceeded with his rational treatment, carrying out the first operation on his own son, Ralph (aged 28) who had been ill since 1905, but he died 4 days later. However, Holmes never admitted this in print, and he lied about the history of his radical new procedure: 'The first patient that I performed appendicostomy upon was a boy of 20 who had been sick only two years.' (Holmes, 1922c: 80). This patient, 'A.H.' was in fact the second patient to have the operation, conducted by Holmes on 25 July 1916 at Lakeside Hospital in Chicago, despite the fact that his first experience with this technique had ended in tragedy.

A very small incision was made as if for an appendectomy, and the appendix brought into the wound. No gross pathology was observed in this region. The appendix was rather large but not inflamed. About twothirds of the mesentery of the appendix was ligated and cut away. The cecum was stitched to the peritoneum and fascia of the abdominal wall on both sides of the wound. The short incision was then closed around the appendix in layers with fine lasting catgut. The skin was closed and last of all the protruding portion of the appendix was cut off a quarter of an inch from the skin, one half at a time, and fastened open with silk stitches holding the mucosa and serosa together and fastening both to the skin. (Holmes, 1922c: 80-1) Penetrating the resulting stoma with a glass-tipped rubber hose, Holmes performed an irrigation of the caecum using water with magnesium sulphate, and then later taught the patient and his father how to do the daily irrigations.

During the following six months his father irrigated the colon through the appendix with water, in which a small amount of magnesium sulfate was dissolved. The patient sat on the stool in the bath room. The ten-quart pail was hung about five feet above the stool and connected by an ordinary rubber tube with a dull glass point to the appendix. When the irrigation was begun the father read aloud to his son, thus passing the time profitably.

According to Holmes, the patient was less delusional and much improved after the operation even five years later, though there remained a 'pronounced mental defect' (Holmes, 1921b: 233).

Holmes eventually came to believe his treatment would work best and perhaps even cure dementia praecox if it was performed either before or directly after the first psychotic break. Patients who had been sick for many months or years -such as his son Ralph -would probably not be helped very much by the procedure. Like Henry A. Cotton, Holmes believed that early surgical intervention could prevent the chronic course of the illness (Scull, 2005: 45-6, 57).

Holmes operated on a third dementia praecox patient, a 21 year-old male, on 3 October 1916 at Lakeside Hospital. The young man had become ill in March 1915 and was removed from Elgin State Hospital in Illinois for the experimental surgery; on recovery he was returned to the hospital. No improvement in his condition occurred until 5 months of daily irrigations had taken place. After being released in March 1917, the patient continued the irrigations himself at home and made a full recovery. (Holmes, 1919a(Holmes, , 1922c: 82): 82). Holmes enthusiastically used this patient as living proof of the correctness of his new treatment, mentioning his case in many of his later writings and encouraging him to give testimonials of his cure at professional meetings to Holmes' medical colleagues. Holmes would routinely publish the names, addresses and intimate details about the lives of the patients who received this experimental treatment so that others could verify his new treatment and possible cure of dementia praecox.

Shortly after operating on this young man, Holmes rushed into print, in late October 1916, a description of his new rational treatment for dementia praecox, claiming prematurely that he had operated on two patients and that they were both 'apparently improved' (Holmes 1916: 702). Holmes began to convince his colleagues of the soundness of the new experimental treatment. Two more dementia praecox patients were operated on for Holmes at Cook County Hospital by Wyllis Andrews, M.D. In all, by 31 December 1916, Holmes reports that five patients had received this experimental treatment.

Two of the operated patients are now at the Elgin State Hospital where the irrigations are being continued. Three of them are at home. The first patient was operated on in July, the last one in December. All of them have improved in weight, and the blood pressure has approached normal. The mental condition is said to be better. 4 The Psychopathic Research Laboratory, 1917-18

Holmes had carried out the operations after his work with Retinger was abruptly halted on 1 April 1916 when private funds ran out and all their laboratory equipment was taken from the Psychopathic Hospital space and returned to Cook County Hospital.

After the demise in late 1916 of Holmes' dream of the Cooperative Research Laboratory, he lobbied hard for a new laboratory and convinced the following to approve his proposal: Joseph Miller, M.D., the medical director of Cook County Hospital, John Nuzam, M.D., the head of the clinical laboratories at Cook County Hospital, Adam Szwajkart, M.D., the Director of the Psychopathic Hospital, and the Board of Commissioners of Cook County, Illinois. On 18 April 1917 the top floor of the Psychopathic Hospital in Chicago was formally designated the Psychopathic Research Laboratory of the Psychopathic Hospital, Cook County Hospital. The space contained a full hydrotherapy suite with four continuous tubs, but the facility had never been used. Holmes and his colleagues covered the tubs with tall laboratory tables that were to be worked at while standing. One large room was filled with ten beds for experimental subjects with dementia praecox. Other large rooms became laboratories for bacteriology and physiology, and a smaller one became a 'blood laboratory'. An 'animal house' was constructed on the roof (Holmes, 1922c: 87-8).

The Psychopathic Research Laboratory remained open for only ten months, until February 1918. The entry of the USA into the war in Europe in 1917 led to the reallocation of funds by Cook County and disruptions in medical and nursing staff. Holmes served as its Director, and Retinger was hired full-time as its biochemist. The remainder of the clinical staff were: Horry Matthew Jones, bacteriologist, who had received his PhD in bacteriology from Northwestern University in 1916; Walter Ford, M.D., psychiatrist; H. C. Stevens, PhD, M.D., psychologist; James Henderson, blood morphologist; Paul Headland, clinical assistant; and Leola Sexton, A.B., entertainment and re-education. During its brief existence, the laboratory admitted 30 patients to its experimental research inpatient unit, but 10 remained only a few days before being discharged or sent elsewhere because they were not suffering from dementia praecox or because permission for experimental treatments could not be gained from parents or guardians. Of the 20 genuine dementia praecox patients treated, 10 were discharged as 'recovered' or 'greatly improved', 3 were committed to state hospitals at the request of the researchers, and 7 were still residing in the laboratory when it closed.

Three experimental treatments were tested. The first consisted of administering calcium lactate with meals to bolster calcium levels in the body. Holmes had read clinical reports that indicated a lack of calcium led to muscle spasms, including those in the intestines such as spasms of the sphincter known as the 'ring of Cannon' that Holmes had come to believe was causing the caecal stasis in dementia praecox patients. No improvement was ever found with this treatment. A more promising remedy was intravenous injections of saline, which led to improvements in the symptoms of 2 of 18 dementia praecox patients on whom it was administered. But the third and most effective treatment was, of course, appendicostomy and daily irrigation of the caecum and colon. Eight patients underwent this surgery and procedure, and all were among the 10 discharged as 'recovered' or 'greatly improved' (Holmes, 1918d).

But right from the start, all was not well in the laboratory. During the official opening night reception Sidney Kuh, a powerful physician with Cook County Hospital, made remarks critical of Holmes and his research programme and this emboldened others who were irritated by Holmes' fiery temperament. Prominent among these was Julius Retinger, who began to resent Holmes. Two months into the operation of the laboratory, Holmes wrote Retinger an emotional letter (4 June 1917), confiding at first, 'You know that I love you like a son and admire you and your splendid intellect.' But Holmes then issued a sharp rebuke for the 'very many deficiencies' in Retinger's work 'due to neglect' and ended with a threat: 'You must be more attentive to your own work, less conspicuous elsewhere, or I shall be obliged to terminate our business relations and I shall do it on June 30.' 5 The chill in relations between the two men progressed to the point that Holmes fired Retinger in December 1917. 'My laboratory has had a sort of revolution and Retinger is discharged', Holmes wrote to one of his most generous financial backers, George Fuller. 'The trouble began in what Dr Kuh said the night of the opening Apr. 18, Dr. Retinger took his cue from that and began intriguing for my displacement and his own elevation.' 6 Retinger also did not get on with the newly hired bacteriologist, Horry M. Jones. On 5 September 1917 Holmes wrote to Adam Szwajkart, the director of the Psychopathic Hospital, that 'During the past three months there has been a constant condition of petty quarrelling between Dr Retinger and Dr Jones and it has been necessary for me to take them aside and discuss matters with which the laboratory has absolutely nothing to do.' Holmes then asked Szwajkart to dismiss Jones and keep Retinger. 7 But there may have been another reason for Holmes writing this letter: Jones had participated in the same research as Holmes and Retinger, but had arrived at entirely different interpretations of the data. Furthermore, Jones had been vocal in raising serious methodological questions about the scientific soundness of their work. Jones was dismissed in September 1917 and replaced by Enrico Ecker. Stunned, Jones wrote to Adolf Meyer for guidance. The letter is worth quoting in its entirety: Dear Doctor Meyer:-I have just been summarily dismissed from the Cook County Hospital Psychopathic Laboratory by Dr Bayard Holmes for my inability to agree with him and his chemist regarding their theory on the etiology of Dementia Praecox. However, during the investigation, I have collected a mass of data and observations, which I am anxious to publish, although directly opposed to every phase of their theory. For example, some Xraygraphs to which I have access, entirely disprove Dr Holmes statements in regard to the cecal-stasis caused by the constriction of the ring of Cannon. This statement although not fundamental to their theory has been made so often, and if true, ought easily to be proved by them with actual Xraygraphs, instead of Dr. Holmes' free-hand drawings.

Early in the investigation I made a comparison of the bacterial flora of the stools of normal controls and of Dementia praecox patients. Among the organisms isolated for study was found one which I later proved was able to produce histamine from histadine and which proved to have all the ear-marks of a B. aminophilus intestinalis of Berthelot and Bertrand, an organism which Dr. Holmes now refers to so freely as being a constant inhabitant of the intestinal tracts of Dementia Praecox patients. This organism, which, as my daily records will show, was isolated from the stool of the Chemist himself, was then mixed in definite proportions with feces and plated on a specially prepared or selective medium and found to be easily recovered and recognized directly on the plates. (In all the specimens examined, thirty-eight counting the controls, no other organism was found which in pure culture produced detectable quantities of histamine from histadine.) This selective medium was then used for direct plating of the stool of the patients, and in no case was it possible to recover a single colony of this organism on plates showing as high as five hundred colonies per plate with ten plates to each sample of stool. In other words, I tried hard to find the organism. The chemist, however says he finds histamine in the stools of the patients but I am able to say positively that since I have been here he has not examined one single specimen from normal controls to see if it may not also be found in persons other than Dementia Praecox patients, in spite of the fact that I detected in a normal stool and demonstrated in his presence a substance giving the Pauly reaction and the oxytocic reaction of tyramine, a substance produced by the same peculiar action of the histamine producing organism.

At present I am looking for a position where I shall not be forced to pervert my laboratory findings to fit some preconceived theory, but I am writing to you primarily to learn your opinion of the worth of this theory in the light of your knowledge of the disease, and also for your advice as to how I can get the data I have accumulated into print.

Very sincerely,

[signed] H. M. Jones 8 Meyer's response -if any -has not surfaced. Jones quickly composed a scientific paper that has stood the test of time as the only serious attempt at scientific criticism of the research of Bayard Holmes [START_REF] Jones | A determination of the numbers of histadin decarboxylating organisms in the feces of dementia praecox as compared with the numbers in normal feces[END_REF]. The editors of the Journal of Infections Diseases received the paper from Jones on 5 October 1917, less than a month after he was dismissed. By early 1919 he had found a position in the Department of Pathology and Bacteriology, University of Illinois, College of Medicine, in Chicago. But it is clear from the information contained in this letter that Holmes' own dictum, 'the laboratory will show up a false teacher in the shortest time', had come back to haunt him.

The Yankton experiment

Ignoring the serious scientific objections to his theory of dementia praecox, Holmes continued to dispense his cure. In the autumn of 1917 he received a request for a consultation from Leonard C. Mead, M.D., the Superintendent of the Yankton State Hospital in South Dakota. He wrote concerning the misfortunes of the Lauer family who had a son and two daughters in his hospital, all with dementia praecox. Holmes offered to go to Yankton and help any way he could. In the latter half of November 1917 Holmes lectured to the medical staff of Yankton State Hospital on his theory of dementia praecox and his therapeutic successes reached through surgery and irrigation of the caecum. Impressed by these apparent medical breakthroughs, Mead and his medical staff agreed to co-operate in a grand experimental test. Seven dementia praecox patients underwent the appendicostomy: the three afflicted members of the Lauer family, and four other inpatients. In a two-year followup assessment of the treatment, the results were mixed. Of the members of the Lauer family, one (the son) died from peritonitis following the operation, one made no improvement whatsoever, and the third, who had just been admitted for the first time, completely recovered and by September 1919 only took an 'occasional irrigation'. Of the four unrelated patients, one female recovered after 8 months and was working and doing well; one male recovered after 9 months and was also working and doing well; another female showed no improvement, and a final female improved after 18 months but was still not well and had to be taken care of at home (Holmes, 1919b).

By the time of the closing of the Psychopathic Research Laboratory in February 1918, Holmes or other surgeons who had been instructed by him had performed appendicostomies on at least 21 dementia praecox patients. Neither Holmes nor his colleagues performed any more surgical procedures on dementia praecox patients after this date. However, Holmes instructed a surgeon in Orlando, Florida, to conduct one last surgical treatment in 1919, bringing the total to 22 patients. 9 Just a few months later, in July 1918 at the Trenton State Hospital in New Jersey, Henry A. Cotton conducted the first of 645 major surgical procedures (laparotomies, colectomies, hysterectomies, thyroidectomies, and so on) over the next 14 years, one-third of them on dementia praecox patients, one-third on manic-depressive patients, and one-third on patients with milder psychiatric illnesses (Scull, 2005: 308). By Cotton's own reckoning, 25-30% of these procedures resulted in the death of the patient. Of the 22 dementia praecox patients operated on by Holmes or his colleagues, only two died from complications following surgery, confirming the claim by Holmes that his surgical treatment for treating mental illness was superior to that of Cotton's, which 'crippled' his patients:

A small number of cases have been treated by this method [appendico s t o m y ] under favorable conditions, but too many have been 'operated on' and then left without carrying on the months long irrigation of the colon and years long re-education of the crippled patient. (Holmes, 1921a: 137).

'A sad fate fulfilled … a factor in the great call for more knowledge' 'I shall be at Fairhope, Ala., for the next few months', Holmes writes to the editor of Medical Life, Victor Robinson, on New Year's Day 1923. 'I have been quite sick and must lay up.' 10 He revealed he had been suffering from a 'toxic myocarditis' for quite some time. In fact an infection of his left hand had developed into an inflammation of his heart and had rendered him a semi-invalid by August 1922. Holmes knew the end was near. He gathered his personal papers relating to his scientific and political careers and donated them to the John Crerar Library at the University of Chicago. He also wrote a farewell address for those interested in his research programme on dementia praecox that was published posthumously. 'And so it has come to this. I can personally do no more. Spiritually and physically I am disheartened . . . I am down and out, but not melancholy' (Holmes, 1924: 235).

While Cotton of Trenton State Hospital in New Jersey had, due to his own self-promotion, become a medical celebrity in the popular press in America for his surgical treatment of the focal infections that caused the insanities, Holmes followed the traditional ethical path of physicians of his era and resisted such a strategy. Despite his keen knowledge of the power of the press, which he had used to his advantage in his political campaign for mayor of Chicago and his public health crusades, Holmes did not seek out journalists to sell his cure. But sticking to the tried and true path of aiming his publications at medical colleagues ultimately failed him. As his life neared its end, Holmes suffered intensely from the fact that his own major medical contributions -his hypothesized cause and its rational treatment for dementia praecox -had been resoundingly ignored by the scientific community. The fact that Cotton never referenced him in any of his publications, nor gave him credit for the priority in developing surgical treatments for dementia praecox, must have particularly galled Holmes.

Holmes became weaker, and he eventually died at his Alabama home on 1 April 1924. He was buried in the cemetery in Fairhope. On the front page of The Fairhope Courier [START_REF] Dr | Bayard Holmes passes to rest[END_REF], an article 'Dr Bayard Holmes Passes to Rest' is prominent. It contains a description of a memorial service held at his home. 'No man ever gave more than he gave -no one ever loved more than he loved his son -no one served better than he served', said Mrs John O'Connor, a friend and neighbour from Chicago. 'His ambition had been centered in this son, so he retired from his practice to minister to him in the home they had built together -a great man -who had made the great sacrifice in the eyes of the world' 11 A letter to the editor from a Fairhope neighbour also identified the agony of the father with the fate of the lost son. 'I knew Dr Bayard Holmes in Fairhope, Ala., know his beautiful home, and know him by sight only. There was something sad about it all, and it must have been the "mental" illness of his son that made of him a "recluse" in Fairhope.' 12 But perhaps it was not the mental illness of his son, but the gnawing memory of how it had ended, that had eventually driven Holmes to retreat into his Alabama sanctuary. Ralph had died one month after his father's decision 'to act upon the rational indications' of his theory of dementia praecox 'without delay'. One week after Ralph's death, Adolf Meyer had composed a letter of condolence to Holmes. 'A sad fate fulfilled -unlike many others, having been a factor in the great call for more knowledge', he wrote. 13 We can only wonder if, at the end of his life, when reflecting on Ralph, Holmes may have wished for a more patient temperament and moderation in his quest for more medical knowledge. Martyred by his father, the son cannot tell us if the 'great sacrifice' was worth it.

Acknowledgments

The research for this project could not have been completed without a generous Faculty Development Fund grant from DeSales University. The author wishes to thank Dr Karen Walton, Provost and Vice President for Academic Affairs of DeSales University, and Dr Boyce Jubilan for approving the funding of this project. The author also wishes to express his gratitude to the helpful staff at the following seven institutions: the Special Collections Research Center, Regenstein Library, University of Chicago; the John Crerar Library, University of Chicago; Countway Library of Medicine, Harvard Medical School, Boston; Alan Mason Chesney Medical Archives of the Johns Hopkins Medical Institutions, Baltimore; the History of Medicine Division, National Library of Medicine, Bethesda; The Historical Library of the College of Physicians, Philadelphia; and the Rare Book and History of Medicine Collection of the New York Academy of Medicine, New York City.

Institute voted to fund the project in a meeting on 17 December 1915. Holmes and Retinger accordingly began slanting their publications to signal their approval of Billings and his ideas.

The 'Contract of the Cooperative Research Laboratory at Chicago State Hospital' was modified, extended and then signed on 3 April 1916. to the crowded conditions at the Chicago State Hospital, the building was re-occupied by patients. Holmes was furious. 'The contract failed . . . because of the neglect of the director of the Sprague Institute, Dr. H. Gideon Wells, or of the trustees of the institute behind him.


Richard Noll
email: richard.noll@desales.edu

Keywords: autointoxication theory in psychiatry, Bayard Taylor Holmes, dementia praecox, focal infection theory in psychiatry, surgical treatments in psychiatry Infectious insanities, surgical solutions: Bayard Taylor Holmes, dementia praecox and laboratory science in early 20th-century America

, a Chicago physician and surgeon with no psychiatric training, conducted both library and laboratory research on dementia praecox, as described in Part 1 of this two-part study. By late 1915 he believed he had found support for a focal infection theory of its aetiology -an ergot-like toxaemia caused by faecal stasis in the caecum. Holmes was also the editor of what is believed to be the first medical journal named after a psychiatric disorder: Dementia Praecox Studies. Part 2 will describe Holmes' adoption of a rational therapy (using it first on his son, who died), and his founding of a Psychiatric Research Laboratory.

the father placed Ralph in a private institution, 'where he was locked up, fed and restrained by pounds, actually pounds of sedatives'. 2 The diagnosis was dementia praecox. The boy would never recover from this illness, and it is listed on his death certificate as the official cause of his death at Lakeside Hospital in Chicago on 23 May 1916. 3 Many death certificates of that era blamed dementia praecox for extinguishing the flame of life in mostly young, mostly male and mostly forgotten insane persons such as this one. However, unlike most victims of dementia praecox whose lives have faded into oblivion, the first psychotic break of Ralph Loring Holmes catalysed a chain of events in a heretofore lost chapter in the larger story of early twentiethcentury American medicine: the laboratory science approach to discovering the causes of mental illnesses such as dementia praecox, and the development of rational treatments based on such laboratory findings.

The psychotic illness of Ralph Loring Holmes enters the history of American medicine and psychiatry through its influence on the life of the boy's father, Bayard Taylor Holmes (1852Holmes ( -1924)). 4 Holmes was personally devastated by his son's illness. His anguish was exacerbated by feelings of impotence, for although his professional life was devoted to improving medical education in Chicago, he had a complete lack of expertise in psychiatry. Holmes, however, had a combative nature and decided to tackle his ignorance and his son's illness head-on. Weary of relying on the advice of colleagues and some of the most respected psychiatrists in America while watching his son deteriorate further, Holmes semi-retired from his surgical practice and his position as Professor of Surgical Pathology and Bacteriology at the College of Physicians and Surgeons in Chicago to care for his son himself. He also vowed to use his scientific expertise to find both a cause and a cure for dementia praecox. He soon became a prominent advocate for reforms in the institutional care of the mentally ill, compiled a bibliographic collection of more than 8000 international scientific articles, dissertations and books concerning laboratory studies of dementia praecox, and from 1918 to 1922 was the editor of what is believed to be the first medical journal named after a psychiatric disorder: Dementia Praecox Studies.

Using equipment and bench space loaned by medical colleagues, in January 1915 Holmes began his own laboratory studies of dementia praecox. Within a few months, to his satisfaction, he hit upon a viable organic theory of the cause of dementia praecox. In the spring of the following year, 1916, he developed and experimented with a rational treatment based on this theory, applying it first on his own son who was suffering from dementia praecox, and testing it further on additional patients with dementia praecox between April 1917 and February 1918 at an experimental inpatient unit known as the Psychiatric Research Laboratory of the Psychopathic Hospital, Cook County Hospital, in Chicago, Illinois.

The organic aetiology of dementia praecox which Holmes believed he discovered was grounded firmly in medical theories that were popular during World War I: autointoxication or focal infections located somewhere in the body that reached the brain and produced severe mental and physical disorders. His bibliography of publications in support of the autointoxication or focal infection theory of dementia praecox is perhaps the most comprehensive summary of this obscure literature in the history of psychiatry [START_REF] Holmes | A guide to the documents in evidence of the toxaemia of dementia praecox[END_REF]. Holmes was not alone in positing such a theory: Emil Kraepelin (1856Kraepelin ( -1926) ) himself had speculated in the 5th-8th editions of his textbook, Psychiatrie: Ein Lehrbuch für Studierende und Ärzte, that such a process of autointoxication (Selbstvergiftung), possibly arising from the sex glands (and to which heredity made one vulnerable), was probably the true cause of dementia praecox (Kraepelin, 1896: 439;1913, III/2: 931;1987: 23;1990: 154). The prominence of theories of autointoxication and focal infection in psychiatry in the early twentieth century has been surveyed elsewhere [START_REF] Jahn | Die gastrointestinalen Autointoxikationspsychosen des spaeten 19. Jahrhunderts[END_REF][START_REF] Noll | Historical review: autointoxication and focal infection theories of Dementia Praecox[END_REF][START_REF] Scull | Madhouse: A Tragic Tale of Megalomania and Modern Medicine[END_REF] and need not be elaborated here.

The rational treatment that Holmes derived from his specific theoryabdominal surgery and daily colonic irrigations -claimed the life of the first dementia praecox patient in history to receive it as an experimental procedure. Ralph Loring Holmes died at the hands of his own father, a medical misadventure known at the time by family friends and some prominent medical colleagues, such as Adolf Meyer (1866Meyer ( -1950)), but which has largely remained secret for almost 80 years.

In his recent book, Madhouse: A Tragic Tale of Megalomania and Modern Medicine, Andrew [START_REF] Scull | Madhouse: A Tragic Tale of Megalomania and Modern Medicine[END_REF] details the story of Henry A. Cotton (1876A. Cotton ( -1933) ) of the Trenton State Hospital in New Jersey and his reliance upon radical surgical procedures to alleviate or 'cure' persons afflicted with severe mental disorders caused by focal infections arising in the mouth (from rotting teeth), the colon, the stomach, the thyroid, the cervix and other areas of the body. The story is a horrific one. However, although Scull's tale is instructive about the reception and application of focal infection theory in America, it is incomplete. For example, although Cotton worked under Kraepelin in Munich for two years and certainly must have known of Kraepelin's speculation that dementia praecox was probably caused by an autointoxication, this influence on Cotton's later thinking is not explored. But more importantly for our purposes here, nowhere in Scull's volume is there a mention of Bayard Taylor Holmes or the fact that it was Holmesnot Cotton -who was the first to attempt the surgical treatment of dementia praecox.

There is no evidence that these two men met or corresponded. However, Holmes knew of Cotton's work by the early 1920s and was supportive of it, although he criticized the emphasis on the removal of teeth, organs or tissues rather than the daily colonic irrigations that his method offered (Holmes, 1 9 2 1a: 137). Cotton never mentions Holmes in his publications, but probably knew of Holmes through his many publications or from their mutual colleague, Adolf Meyer. Like Holmes, Cotton produced two sons, performing abdominal surgery on the second, Adolf Meyer Cotton, in a preventive measure to halt the development of any mental disturbance later in life (Scull, 2005: 58). He had already extracted the permanent teeth of both sons and, later, his wife. Unlike Cotton, Holmes had a deeply personal stake in finding the cause and cure of dementia praecox. Unfortunately, he suffered the sacrifice of his own son to achieve it. But any parent of a child with a devastating chronic mental illness would understand his complex motivations, for what is done out of love is beyond good and evil.

What follows, therefore, is essentially a contextualizing preface to Scull's gothic tale: the biographical and scientific case history of a forgotten man in the history of psychiatry. An examination of the life and work of Bayard Taylor Holmes provides us with a narrative perspective through which to view the application of early twentieth-century laboratory medicine to the devastating problem of dementia praecox. The literature in the history of psychiatry currently lacks scholarly studies of the important experimental researchers of dementia praecox during that era. In order to comprehend the rationale for his aetiological theory of dementia praecox and his treatments for it, I explore the various stages of his research programme in great detail. Such a narrative, I believe, also gives us insight into the creative space opened in psychiatry by theories of autointoxication and focal infection, a rich field of possibilities for medical experimentation that, in the pre-antibiotics era, perhaps could have only logically ended with surgical tragedies such as those brought about by Holmes and Cotton. Perhaps the same case could be made for the rise and fall of psychosurgery, when surgical solutions rationalized by basic neuroanatomical and neuropathological research in animals and humans captured the imagination of psychiatrists in the mid-1930s [START_REF] Pressman | Last Resort: Psychosurgery and the Limits of Medicine[END_REF]. It is useful to remember, as Joel Braslow (1997: 4) argued, that 'during their heydays … most of the therapeutic practices … generally conformed to standards that constituted legitimate evidence for efficacy.'

Additionally, the story of Bayard Taylor Holmes also documents the influential role played by Adolf Meyer in the tacit promotion of focal infection theory in American psychiatry through his personal contacts with Holmes and Cotton and his uncritical acknowledgement of their rational treatments. Meyer is anchored at the centre of the Holmes story just as he is in the Cotton story, with not only Holmes but two of the researchers working under him, Julius Retinger and H. M. Jones, reaching out to Meyer for support at various stages of their research on the causes and treatments of dementia praecox.

In the following, I allow the events of the story of Bayard Taylor Holmes to unfold without significant embedding in the secondary scholarly literature. To keep the focus on Holmes, I make only occasional reference to the activities of Cotton as provided by [START_REF] Scull | Madhouse: A Tragic Tale of Megalomania and Modern Medicine[END_REF] in his illuminating volume of narrative history. My intention is to punctuate the need for future scholarly studies of focal sepsis in early twentieth-century medicine, to link Holmes and Cotton, and to treat these two men equally as flawed pioneers of biological psychiatry.

Why have Holmes and his Dementia Praecox Studies been forgotten?

There is a revelatory silence in the literature of the history of psychiatry about Bayard Taylor Holmes, his journal, his laboratory studies of the aetiologic and pathologic processes of dementia praecox and the experimental treatment unit in Chicago. All the major histories of psychiatry completely ignore him (for example, [START_REF] Shorter | A History of Psychiatry, from the Era of the Asylum to the Age of Prozac[END_REF][START_REF] Shorter | A Historical Dictionary of Psychiatry[END_REF], and there are no publications that acknowledge his role in the story of the American l a b o r a t o r y science response to dementia praecox. The last scholarly publication devoted to Holmes and his place in the history of medicine appeared more than 20 years ago, and it, too, ignores his scientific solutions to the cause and cure of dementia praecox [START_REF] Beatty | Bayard Taylor Holmes -a forgotten man[END_REF]. Indeed, even in his own time, neither his publications nor those of his research team in Chicago were cited by prominent figures in psychiatry and neurology. Why?

First and foremost, his professional credentials as a surgeon and bacteriologist and his utter lack of formal training in psychiatry may have been reason enough for the prominent alienists of his day to disregard Holmes and his work. Hence, with the passage of time, the historical trail grew cold. 'I know very well that I have no education or University training, such as your colleagues have, and that it is ridiculous for me to tell you what I think of your letter', he wrote to his old acquaintance Adolf Meyer on 19 February 1912. 5 But perhaps more distasteful to alienists than a surgeon dabbling in psychiatry, Holmes had made it quite clear in numerous opinion pieces in medical journals such as The Lancet-Clinic from 1910 until his death in 1924 that he detested the psychiatric profession for its lack of interest in laboratory science and for making false claims to the unsuspecting public about scientific knowledge of causes and effective treatments. The frustrating experience of trying to find competent help for his son led him to charge that the psychiatrists of his time were not true physicians, but merely 'keepers': … I am shy at using psychiatrist for a man who devotes himself to the professional custody of the crazy and yet denies that they suffer of disease or that there is any need of pathological study of their condition or any hope of cure … I prefer to term them keepers of the insane rather than physicians. It seems to me that a group that denies to dementia praecox a place among diseases and disparages it by relegating it to the 'reactions' can not claim to be psychiatrists in the medical sense. (Holmes, 1922a: 120) This did not win him the respect of psychiatrists, and they responded by refusing to cite his published work and by leaving him out of the histories of their profession that they would subsequently write. Additionally, Holmes was exceptionally out of step with the changing political tide in professional psychiatry by being a vocal sceptic of Sigmund Freud and psychoanalysis. 'It is a distinctly mystical theory,' he wrote in 1914, 'insusceptible of either proof or refutation' (Holmes, 1915a: 96). Holmes also rejected the Meyerian notion that dementia praecox, like all other mental disorders, was a 'reaction' to psycho-biosocial forces. He additionally believed Meyer used a deceptive style of idiosyncratic psychiatric jargon to divert attention away from the fact that little laboratory research on dementia praecox was being conducted in the best psychiatric institutions in the country. 'You are probably the most respected man in psychiatry in the United States and what you say ought to mean a lot to me', Holmes wrote to Meyer in 1912, just before accusing him of being deliberately evasive: 'As a matter of fact, I cannot understand hardly anything in your letter and I believe that some of it, in spite of its interrogatory form, is designed to deceive.' 6 Holmes (1916a: 983) was also a critic of eugenics, which he referred to as a 'pseudoscience'. This, too, set him apart from contemporary trends in science and from prominent figures in psychiatry and neurology associated with the Eugenics Records Office such as Meyer and E. E. Southard (1876Southard ( -1920)), though he maintained superficial professional contacts with both these men.

'The laboratory will show up a false teacher in the shortest time'

Bayard Taylor Holmes found his way to medicine rather late in life. He was 30 years old when he entered the Homeopathic Medical College in Chicago in the autumn of 1882. Having spent the previous ten years teaching science in the schools of Kendall, De Kalb and La Salle counties in Illinois, Holmes began an aggressive self-education programme that went far beyond his formal training. He received his M.D. from the Homeopathic Medical College in 1884, interned for 18 months at Cook County Hospital, then entered the College of Physicians and Surgeons in the autumn of 1885 for further medical training. He received his second M.D. from this institution in the spring of 1888, just before his 36th birthday.

Holmes began his training just as the bacteriological breakthroughs of Robert Koch and others offered the possibility of challenging new career paths for scientifically ambitious medical students. Although he was already no stranger to microscopic work and was, of course, aware of the work of Pasteur and Koch, a single chance event steered him in the direction of bacteriology. While on his way to a series of histological lectures at the Rush Medical College in the summer of 1883, Holmes happened to see a notice for a lecture on tuberculosis accompanied by an autopsy to be given by W. T. Belfield at the County Hospital Morgue. Having just returned from Europe, Belfield summarized the latest developments in bacteriology. The lecture ended with Belfield inviting the medical students in the audience down to his side to observe as he squeezed fluid from the lungs of a cadaver, smeared a specimen from it on a glass microscope slide, then gave these curious students their first look at Bacillus tuberculosis.

Profoundly moved by the experience, Holmes initiated a course of activity that eventually led to a position in 1885 as an assistant to Christian Fenger (1840-1902), a noted pathologist who had introduced Lister's antiseptic operative methods to the staff of Cook County Hospital in 1878 and who was then Professor of Surgery at the College of Physicians and Surgeons in Chicago [START_REF] Herrick | Christian Fenger as I knew him, 1885 to 1902. A study in personality[END_REF]. Holmes had made an impression on Fenger in 1884 when he was the first to show Fenger microbes growing in nutrient material. Fenger had had no experience with the techniques of cultivating bacteria, and he responded to the sight with 'childlike delight' (Hektoen, 1937: 5). Holmes' bacteriological work and his association with Fenger opened doors for him in Chicago. In 1889 Holmes became attending surgeon at Cook County Hospital, and in 1891 he was appointed Professor of Surgical Pathology and Bacteriology at the College of Physicians and Surgeons. Holmes personally oversaw the design and construction of a six-storey laboratory building at the College, and his advocacy of laboratory science in medicine influenced medical training not only at the College but also at other medical schools in the USA. In the opinion of Holmes, a professor of medicine held little credibility unless he could hold his own at the laboratory bench. 'A man can easier preach without being converted', Holmes writes, 'than he can preach without being inspired, and the laboratory will show up a false teacher in the shortest time' (Beatty, 1981: 123).

Together with Fenger, Holmes wrote 'Antisepsis in abdominal operations. Synopsis of a series of bacteriological studies', published in the Journal of the American Medical Association in October 1887 [START_REF] Fenger | Antisepsis in abdominal operations. Synopsis of a series of bacteriological studies[END_REF]. This was Holmes' second publication and it is remarkable for introducing two professional preoccupations that became very personal ones. Indeed, during the years of World War I, they would frame the fateful trajectory of his work on dementia praecox: infections as causes of disease and abdominal surgery as a cure of disease.

'130,000 pitiable wrecks' Bayard Taylor Holmes married Agnes Anna George on 14 August 1878. Their first child, Bayard Taylor Holmes, Jr, was born in 1879 and, following in the tradition of his namesake, became a physician in Chicago. Their only other child, Ralph Loring Holmes, was born in Chicago in 1887. He was a highly intelligent young man who could read both German and Latin, and spoke German fluently in addition to his native English. 7 Ralph, too, was expected to become a physician. However, it was during the middle of his first year of medical school that Ralph was unexpectedly disabled by his illness. Unfortunately, he then quickly became, as his father put it in 1918, one of 'the 130,000 pitiable wrecks' suffering from dementia praecox who were periodic inmates in approximately 'four hundred hospitals for the insane' in the USA (Holmes, 1918b: 5).

The psychotic breakdown of his beloved younger child awakened Holmes to the extreme prejudice against the mentally ill, not only in society as a BAYARD HOLMES, M.D., 1889 (From Medical Life, 31 (1924), Issue 46, devoted to Bayard Holmes) whole but also among his colleagues, close friends and even his own family. Despite his disregard for Adolf Meyer's professional opinions, Holmes was grateful for a letter Meyer wrote in response to Holmes' increasingly polemical editorials and articles about the deficiencies in the care of persons with dementia praecox. In fact, Meyer's letter was the first response from anyone in the field of psychiatry. Holmes' reply to Meyer, dated 19 February 1912, is worth quoting at length here.

I am grateful to you for the first letter which my editorials or reprints have brought forth. At the end of your letter you refer to the calamity to my son Ralph. A few days after the boy was taken away to Jacksonville, I had a beautiful and helpful letter from Doctor Bertram Sippey [Sippy, a Chicago physician], who had undergone a similar experience. Yours is absolutely the second letter from any person, except Ralph's attendants, in which his existence or misfortune has been mentioned. My own scattered family in their numerous and intimate letters to me have never once during these six terrible years mentioned his name or recognized by holiday token or birthday present his past or present existence. Not one of my medical friends in Chicago and elsewhere, many of whom in their family bereavements or professional misfortunes, have called upon me for sympathy and sometimes for succor, rendered at my own great risk, not one of them have volunteered me by letter or by word of mouth in all these terrible years, one single inquiry for my boy or one suggestion of sympathy or token of support. The dozens of internes and assistants and the hundreds, even thousands of students, and I may say, the public itself which has been entertained so freely at my house, not one of them has ever once written me one word of sympathy or recognition of the catastrophe which ruined my son and has taken away my own zest of life.

In my first helplessness I called on two colleagues, who advised in a cold and fateful manner, and withdrew. I followed implicitly their advice, yet they have never asked me how this advice eventuated. Ralph was put in a private institution, where he was locked up, fed and restrained by pounds, actually pounds of sedatives, as his history shows.

At this time I wrote a letter to the two acquaintances whom I considered most likely to offer helpful advice. They were both men most distinguished in their particular spheres. It would be hard for you to imagine with what anxiety I watched for days and weeks for some answer to those two letters which might reprieve my imprisoned hopes, but until today none ever arrived. Professor Jacques Loeb, of California, likely thought my request impertinent, and in your letter today you say that you sent me literature at the time.

It seems hardly likely to me that had I had a daughter and she had blazonly gone into public prostitution, would my colleagues have been as silent. 8 During the first year of his son's illness, Holmes threw himself into his work and relied on his 'most distinguished colleagues in the United States' for advice rather than doing any reading on dementia praecox himself.

They gave one cheerless and discouraging reply, if they did not hedge or neglect to answer. They agreed to a man that the disease was of unknown pathology, unknown etiology and of an invariably unfavorable prognosis. Hopeless custody was the substitute for treatment.

But when Ralph returned home after spending 8 months in a private sanitarium, Holmes decided to use his expertise to find the cause of his son's devastating illness and to save him by finding a cure. He began visiting psychiatric institutions and was horrified when he finally saw the inmates on the 'back wards':

When at last I discovered the result of the disease, the realization of the victims' pathetic condition threw me into a new frenzy. Terrible as my affliction was already my agony had not yet begun. So this was to be my son's end! (Holmes, 1921a: 120) Holmes gradually retired from teaching but continued his medical practice and began a review of the medical literature on dementia praecox. His first impression of the scientific status of psychiatry appalled him.

It will be impossible for you to imagine my astonishment and confusion on reading text books, journals and monographs to find that in this branch of medical literature, the same method, the same argument and the same obscurity prevailed as in the literature of religion and occultism. 9 By 1920 Holmes had compiled more than 8000 references on the pathological, biochemical, histological and bacteriological laboratory findings on dementia praecox. He kept these references in a card catalogue which he donated to the John Crerar Library at the University of Chicago. This database would prove to be of decisive importance to Holmes when he returned to the laboratory to do the critical work himself. Holmes never lost his certainty that clues to the aetiology, prophylaxis, therapy and eventually cure of dementia praecox were somehow buried in this gigantic and seemingly disconnected body of evidence. To Holmes, continual consultation of the medical literature was as necessary for a practising physician as clinical experience and basic laboratory skills [START_REF] Holmes | Is it desirable and practicable in medical schools to teach methods of investigation in medical literature?[END_REF]. The problem that plagued him for years, however, was how to discern which of the thousands of published laboratory findings on dementia praecox led to the truth about this disease. One new lead after another was followed and then abandoned in favour of the latest new laboratory technique or organic finding. As Holmes frantically tried to master this immense literature and begin his own laboratory studies, the years rolled by and Ralph Loring Holmes continued to deteriorate.

Dementia Praecox Studies

Holmes turned his revulsion for the psychiatric treatment of his son into a public crusade. He was temperamentally well suited for this. As a man of rather benign rural origins, Holmes had been appalled at social conditions in Chicago when he moved there to attend medical school. He was especially angered by the living and working conditions of immigrants and the poor. He involved himself in issues such as the education of illiterate workers, the inspection of safety conditions in factories, and child welfare. He founded an organization called the National Christian Citizenship League which recruited volunteers to engage in various social welfare projects among the destitute of Chicago. His social conscience led him into politics, and in 1895 he was the unsuccessful Chicago mayoral candidate for both the People's Party and Socialists of Eugene Debs, coming in third behind George Bell Swift. 'He is a man of moods', reported a Chicago newspaper in the days following Holmes' nomination, continuing:

The doctor's personal peculiarities are intense. He is a fighter when aroused, and frequently it takes very little to arouse him. He has been known mercilessly to flay with tongue or pen those with whom he differed or whom he thought deserved a flaying as a matter of principle. 10 Three years after his son Ralph became ill, Holmes published his first clinical article with a psychiatric theme when he wrote a warning about the use of chloroform with dementia praecox patients' (Holmes, 1908a). However, it would be several years before he published further clinical contributions in psychiatry. Instead, he used the pages of the Cincinnati-based medical journal The Lancet-Clinic as his bully pulpit and wrote one short essay after another deploring the conditions in state hospitals, demanding more state funding for laboratory research on dementia praecox, and denigrating just about every prominent school of thought in psychiatry. The first eight of these essays appeared in 1910, but Holmes, mimicking Sir William Osler [START_REF] Tigertt | An annotated life of Egerton Yorrick Davis, M.D., an intimate of Sir William Osler[END_REF], used the pseudonym 'E. Y. Davis, M.D.' for them. He continued writing editorials for this journal until 1916. These essays were collected and published under his actual name in two volumes: The Friends of the Insane, The Soul of Medical Education, and Other Essays (Holmes, 1911) and The Insanity of Youth and Other Essays (Holmes, 1915a). Beginning in 1914, Holmes sent out reprints of his articles as circulars under the heading Dementia Praecox Studies. He also became peripherally involved in the mental hygiene movement.

During the annual meeting in Chicago of the Alienists and Neurologists Association, held 10-12 July 1917 -the year after his son's death -Holmes lobbied for the creation of an organization to study dementia praecox (Holmes, 1917). However, although several prominent conference participants signed the initial petition, only Holmes' Illinois colleagues committed themselves to the proposed organization. On 13 July 1917 Holmes was joined by two Illinois physicians, Hermann Campbell Stevens of Chicago and George Michell of Peroria, as elected officers of the Society for the Study of Dementia Praecox. The purpose of the society was 'to stimulate further research and to co-ordinate work already in progress in different parts of the world' (Holmes, 1918a: ii). The main method for achieving these goals was the publication of a quarterly scientific journal that would be distributed internationally: Dementia Praecox Studies: A Journal of Psychiatry of Adolescence.

In the opening pages of the inaugural issue (1 January 1918) of Dementia Praecox Studies, the editors unabashedly expressed their 'faith' in the hypothesis that 'disease of the mind is the result of organic disease of the body', and as 'in spite of the magnitude of this problem there is a great scarcity of books and monographs dealing with the physical, chemical and biologic conditions of the unfortunate victims of this disease', they 'urge the publication of a journal devoted exclusively to the study from the organic point of view, of one part of the field of mental disease, viz., dementia praecox' (Holmes, 1918a: ii).

Dementia Praecox Studies continued to be published through five volumes, ending in 1922 when Holmes' health began to fail. During these five years it included a wide range of articles on dementia praecox, many of them republished or translated from international journals. Unfortunately for Holmes and his colleagues, the journal had little impact in accelerating research. But fortunately for historians, it chronicles the path of his own research in the cause of dementia praecox, the rise and fall of one dementia praecox research laboratory and the failed plans for two others, and the results of the experimental treatment that Holmes devised and believed until the day he died was more effective than anything psychiatry had to offer.

'The blood crisis … is sudden, almost explosive'

Like many physicians of his era who were trained in the new science of bacteriology, Holmes believed that each disease had a single cause and single cure. Rationally discover the cause of the disease in the chemical, bacteriological, haemolytic or physiological laboratory, and a rational treatment or even a cure would soon follow. Dementia praecox would yield its secrets just as tuberculosis, syphilis, yellow fever, typhus and cholera had done in Holmes' lifetime. He was convinced from his earliest bibliographic researches that dementia praecox was a physical disease with an organic, mechanistic aetiology. Psychogenic causes for dementia praecox were not rational ones in his opinion, and therefore he completely discounted them. Holmes could not discount the role of heredity in the insanities, but he felt that these distal influences were secondary to more powerful, ongoing proximal causes in dementia praecox that could be found in living bodies and effectively treated. The theory of the hereditary cause of dementia praecox should, he felt, therefore be taken with a grain of salt. He often illustrated his position by arguing that heredity also had been considered the greatest aetiologic factor in pulmonary tuberculosis and syphilis until the discovery of their respective pathogenic bacteria led to the abandonment of that theory.

By the winter of 1909, Holmes' literature review of laboratory studies of dementia praecox had led him to conclude that 'most of the investigations came to zero for their aggregate result' (Holmes, 1921a: 121). However, he felt that there were eight firm findings in the literature: [START_REF]Ralph Loring Holmes[END_REF] the identifying symptoms of the disease were well described and could lead to a reliable diagnosis after a single observation of the patient; (2) the prognosis for recovery was uniformly poor; (3) spontaneous recoveries were rare; (4) many dementia praecox sufferers improved, and some completely recovered, following an acute infectious disease accompanied by a high fever; ( 5) brain weight was heavier in dementia praecox than normal; ( 6) chronic cases of dementia praecox often manifested left-sided internal hydrocephalus; [START_REF] Holmes | Special Collections Research Center[END_REF] no fundamental histopathology of dementia praecox had been discovered and its existence was often denied; [START_REF] Holmes | AMC. Meyer told Holmes in subsequent correspondence that he did not remember where he had first heard of Ralph's illness, and offered to review Ralph's treatment records from the Psychopathic Ward of the University of Michigan Hospital in Ann Arbor, Michigan. Both Holmes and Meyer then contacted its director[END_REF] in several highly suggestive cases, rapid polycythaemia (an increase in the number of red cells in the blood) resulted in an alleviation of symptoms in dementia praecox, especially if the red cell count increased by 2 million within an hour.

This last finding particularly intrigued Holmes. He had been following with fascination the transformation of the clinical laboratory since 1900 brought about by the serological and immunological contributions of Karl Landsteiner and those of others, such as August Wasserman (1866-1925) and Emil Abderhalden (1877-1950), who followed in his wake. When Much and Holtzmann (1909) published their study of differences in reactivity to cobra venom of the blood of dementia praecox patients when compared with normals, Holmes was encouraged. Blood changes measured in dementia praecox victims were, in Holmes' mind, convincing evidenceespecially to himself -that persons such as his son Ralph were 'really sick' due to a recognized organic disease rather than a psychogenic mind twist or hereditary taint (which, of course, would locate the cause of his son's illness directly in Holmes himself).

Blood held the secret to solving the mystery of dementia praecox. Therefore, in congruence with his training as a bacteriologist, between the years 1909 and 1916 Holmes largely followed a serological programme in his search for a cause of dementia praecox. 11 From this point on he was intrigued by spontaneous rapid changes in the relative numbers of red and white cells in the blood -a phenomenon termed a 'blood crisis' -particularly if they were linked to specific diseases and not found in normals. Holmes found the work of two dementia praecox researchers particularly relevant in this regard. The first, Halvar Lundvall of Lund, had reported in Swedish publications as early as 1907 some initial success in improving the symptoms of dementia praecox patients by injecting them with sodium nucleate (salts of yeast acids used in the treatments of anaemia, rheumatism and gout) [START_REF] Lundvall | Blood-changes in Dementia Praecox and artificial leukocytosis in its treatment[END_REF]. Sodium nucleate had long been known to increase the number of white blood cells (leucocytosis) and had been used by others with success in the treatment of septicaemia and paresis, and the fact that it seemed to work in dementia praecox suggested its symptoms, too, might be due to an infectious process, perhaps even a bacterial one (for a review of this literature, see Holmes, 1915b). The second, Gunnar [START_REF] Kahlmeter | Blutuntersuchungen bei einem Fall von Dementia praecox mit periodischem Verlauf[END_REF] found that very abrupt changes in the relative numbers of white blood corpuscles, red blood corpuscles, and the percentages of the neutrophile leucocytes, lymphocytes and eosinophile cells could be directly correlated to disturbed mental states. 'The blood crisis of Lundvall and Kahlmeter is prognostic of change in the mental symptoms and this crisis is sudden, almost explosive', wrote Holmes (1916b). Holmes was also fascinated by the studies of Willi [START_REF] Schmidt | Adrenalin unempfindlichkeit der Dementia Praecox[END_REF] in which the typically low blood pressure of dementia praecox patients (or so it was assumed at the time) could not be raised by an intramuscular injection of 0.5 cc of 1:1000 adrenalin solution. Holmes (1915c) suggested that adrenalin injections could be a possible diagnostic test for dementia praecox since they produced this paradoxical response.

In January 1915 Holmes returned to the laboratory to do his own serological work on an intermittent basis with a colleague, Peter Gad Kitterman (1877-?). [START_REF] Holmes | Medicine in Ancient Egypt: The Hieratic Material[END_REF] had co-authored a short amateurish monograph on ancient Egyptian medicine. At first they had no laboratory of their own, nor any money for their own equipment, so from 1 January to 1 April 1915 they used a laboratory room at the Ricketts Laboratory in Chicago belonging to Dr H. Gideon Wells, Director of the Otho S.A. Sprague Institute and a researcher at the University of Chicago. This work was conducted during off hours whenever they could steal the time from their busy lives. Holmes knew it was to be the beginning of a long research programme: 'My first thesis was to demonstrate the first evidences of disease in dementia praecox patients and the absence of the same evidence in other patients.' 12 The decisive factor in the return of Holmes to the laboratory was his discovery in late 1913 of the techniques of the Abderhalden defensive ferment reaction and the fact that it has been used diagnostically with some success by European researchers in Germany and Italy. Holmes was particularly convinced by the claims of Stuttgart researcher August Fauser (1856-1938) that Abderhalden's test could differentially diagnose dementia praecox from other disorders and from healthy controls [START_REF] Fauser | Einige Untersuchungsergebnisse und klinische Ausblicke auf Grund der Abderhaldenschen Anschauungen und Methodik[END_REF](Fauser, , 1913a(Fauser, , 1913b(Fauser, , 1913c)). 'Here then, it seems that we have found an almost certain, if not absolutely certain, method of diagnosing dementia praecox', Holmes (1914a: 250) enthused in a short medical report published on 12 February 1914. The dialysing method of Abderhalden purported to recognize in the blood specific defensive ferments (enzymes) connected with specific protein molecules that formed the basis of specific organs or glands. If cells of an organ or gland are injured (such as the brain, liver, heart, lungs, appendix, thyroid or gonads), molecular detritus ends up in the blood and this arouses a reaction, that is, production of the defensive ferments which catabolizes or breaks down these molecules into ones small enough to be eliminated by the body. The specificity of the 'positive reaction' of the ferment in the Abderhalden dialysis method was thought to be directly linked to damage to specific parts of organs, including very specific areas of the brain. For example, a colleague of Holmes consistently found positive reactions in 'the lower part of the motor area in the cortex corresponding to the trunk shoulders, arms and in a lesser degree that representing the head.' 13 Therefore, just through drawing the blood of a patient and analysing it, it was assumed one could 'see' into the living body without opening it surgically and be able to discern focal areas of disease.

At the Ricketts Laboratory, Holmes reported he 'examined the blood of seventy lodging house tramps by the defensive ferment reactions of Abderhalden' and found that 'the blood of the average tramp does not contain ferments that would lead to the diagnosis of dementia praecox' because 'these bloods did not give reactions to the cerebral cortex or to testicle' as had been found and reported in the European studies. 14 From 1 April to 1 August 1915 Holmes continued his studies in a laboratory at Lakeside Hospital in Chicago, but added a new experiment: taking blood from a dementia praecox patient (probably his own son, Ralph) and injecting it into a goat and a rabbit to see if the 'passive transmission of the defensive ferments' could be accomplished. It was. However, since Holmes did not have any blood from a 'recovered patient', the defensive ferment against the cause of dementia praecox could not be injected into an animal for the purposes of producing a serum against the disease to be used later in humans if the animal also began producing these same defensive ferments. 15 However, by his own admission, his application of this complex technique was rather crude. This problem was soon rectified. On 1 August 1915 they were joined by a skilled biochemist, Julius Retinger, PhD (1885-?), who had received his degree from Leipzig in 1913 for a thesis on a method of preparing ninhydrin, an essential component of one of the various procedures for the Abderhalden reaction test. Holmes was given the money to pay for Retinger's services by a grateful former patient. But it was only a small amount, and also Retinger could only work part-time on finding the cause of dementia praecox. The hiring of Retinger coincided with Holmes' move to the laboratory of the Psychopathic Hospital of Cook County Hospital at the invitation of Adam Szwajkart, M.D., its Director. The Psychopathic Hospital, which had opened in 1914 and which occupied a corner of the Cook County Hospital grounds at Wood and Polk Streets, averaged about 80 psychiatric admissions per week who remained only a few days before being released or transferred to various Illinois state hospitals. 16 Thus, Holmes and his new colleague Retinger now had daily access to a rich supply of dementia praecox subjects for their studies.

During the last five months of 1915, Retinger devised an 'improvement' on the Abderhalden method and examined 30 dementia praecox patients, concluding 'it can now be seen that the organs mostly involved in dementia praecox are the cerebral cortex, pons, optic thalamus, genital organs, and the small intestine.' 1 7 With reliably replicated results such as these, the Abderhalden reaction seemed to be a breakthrough in psychiatric research.

The problem with the Abderhalden reaction test, as many researchers soon discovered, was that it was not a quantitative test, but a subjective one. The reaction was 'real' only if tissue from a particular organ gave off a bluish or purplish colour during the process. Some researchers always saw the colour, a few more sometimes saw the colour, but many others never did -and the doubters eventually began to speak out against Abderhalden (Deichmann and Müller-Hill, 1998). By 1920 Abderhalden's defensive ferments had fallen into general disrepute in the USA, although the test continued to be used in Germany for several more decades [START_REF] Kaasch | Sensation, Irrtum, Betrug? -Emil Abderhalden und die Geschichte der Abwehrfermente[END_REF] and, until the end of his life, Holmes would never lose his faith in the method. But by the end of 1915 the Abderhalden test had already outlived its usefulness as a source of new knowledge. Based on Retinger's research, Holmes believed it had repeatedly confirmed which internal organs were implicated in the aetiology or pathophysiology of dementia praecox. Its further use would be redundant. Also, it had not led to the development of a serum that would cure dementia praecox, as had been hoped (Holmes, 1914b). Other methods were needed to detect the true vis morbi of dementia praecox, the cause of the 'blood crisis' and other unusual physiological phenomena.

How Holmes found the cause of dementia praecox

In January 1915, the month that Holmes began his laboratory studies and completed his preface to The Insanity of Youth and Other Essays, he was confident that he had identified a cluster of five organic signs that, taken together, were pathognomonic of dementia praecox: (1) adrenal mydriasis (pupil dilation produced experimentally by two or three drops of adrenalin solution); (2) cyanosis, particularly in the hands; (3) the blood crisis of Lundvall; (4) the positive reactions of the defensive ferment test of Abderhalden for the sex glands, thyroid and cerebral cortex; and (5) the positive response to artifical hyperleucocytosis induced by injections of sodium nucleate (Holmes, 1915a: 44-53). What was missing was an adequate pathologic 'disturber', as Holmes often put it, that would link all these physical phenomena to an underlying cause.

It was Holmes' careful reading of the medical literature that provided him with the clues. While searching the literature for parallels to the paradoxical lowering of the already chronically low blood pressure in dementia praecox patients with adrenalin injections, Holmes found an animal study in which this phenomenon could be produced -but only if the injection of adrenalin followed a prior dosing with ergotoxine (tyramine). Since ergot was then commonly used to induce uterine contractions, Holmes found this same paradox occurred in obstetrical cases. Women who had been given ergot or peturiterin and then injected with an adrenalin solution (5 cc of 1:1000) had their blood pressure lowered. Thus, in the winter and spring of 1915, Holmes began an intense study of the chemistry of ergot and the history of epidemic ergotism. It was this latter literature that led him to consider a connection between the toxic amines of ergot and the symptoms of dementia praecox -an analogical transfer familiar in studies of the history of science in which a previously solved medical problem (in this case, ergotism) serves as a source for solving a new target problem (Thagard, 1999: 134-47), in this case the illness of his son and others diagnosed with dementia praecox.

Of the ten or more toxic amines in ergot described in the biochemical literature of that time, Holmes seized upon histamine (beta-iminazolylethylamine) and indolethylamine as possible pathogens capable of producing the symptoms of dementia praecox. But it was histamine in particular that attracted his attention. In June 1915 he published a paper in which he detailed the striking similarities of the physiological effects of histamine on the body to the symptoms of dementia praecox (Holmes, 1915d). Histamine lowered the blood pressure and produced various effects on the conditions and number of the red and white corpuscles in the blood, similar but perhaps not identical to the blood crisis of Lundvall. And since cyanosis and adrenal mydriasis also occurred in persons who had ingested ergot, four of their five core pathognomonic signs of dementia praecox could be explained by the actions of the toxic amines found in ergot, particularly histamine. The fifth sign, the results of the Abderhalden test, could not be used to detect toxic amines in the blood. Other research methods needed to be found.

Serological analysis allowed for the detection of evidence of an excess of indolethylamine in the blood, but not for histamine. Urine tests were inconclusive. Holmes and Retinger -who had been hired specifically to pursue the ergot-like toxic amine hypothesis of Holmes -found literature documenting the presence of catabolized products of indolethylamine in the urine but, again, histamine could not be detected. Since their theory of the cause of dementia praecox depended heavily on the assumption of 'hyperhistaminemia', they were running out of options. Finally, in work conducted during the latter half of 1915 and early 1916, as Holmes and Retinger told it: 'The examination of the feces alone was left to us. If there had been excessive production of histamine in the intestine from any cause, bacterial or nonbacterial, "endogenous" or "exogenous," some moiety of this excess might be found entangled in the stool.' And so it was. Retinger found no histamine in normal controls and in 'one perfectly sane patient' who had spent three years in an asylum with catatonic dementia praecox. However, in seven patients from the Psychopathic Hospital of the Cook County Hospital, the six dementia praecox patients had excessive amounts of histamine as did one patient with the 'gastric crisis of tabes' (Holmes, 1921a: 130; see also Holmes and Retinger, 1916a). When this last patient was injected with adrenalin the gastric pain stopped immediately and the blood pressure dropped -the same paradoxical effect found in people who had ingested ergot and in dementia praecox patients. This patient provided another clue: they found a tender spot on the right side of the patient's abdomen. Was this the locus of an infectious process that sent poisons to the brain?

Evidence found in the medical literature supported their hypothetical locus of infection. They also learned that other researchers had found that Bacillus aminophilus intestinalis, a bacterium discovered in the caecum, reduced histadine to histamine. All the pieces fitted.

Holmes was now on familiar territory. He was a specialist not only in bacterial infections but also in the organs of the abdomen. His 10-year quest to find a cause and a cure for dementia praecox that had begun in 1906 brought him right back to his major areas of expertise as a physician and scientist. His autodidactic mastery of the gigantic and confusing medical and psychiatric literature, his years of consultations with alienists, neurologists and other medical colleagues, his data resulting from the adoption of new laboratory methods -all of these disparate sources of evidence now made sense when Holmes assimilated them to his pre-existing cognitive schema. Perhaps this trajectory was inevitable. Indeed, as early as 1908 Holmes speculated that, 'It is my opinion that there are many cases of insanity which are due to exogenous toxemia that should be sought for in the infection of some of the natural cavities of the body' and that the infection may be 'possibly of bacterial origin' (Holmes, 1908b: 8).

Similar odysseys by laboratory researchers looking for the causes and cures of dementia praecox had all ended in shipwrecks. The vast majority of those scientists moved on to other, more fruitful voyages at the bench. But not Holmes. Because of the constant reminder of his son Ralph's illness, Holmes was simply not going to give up. He was going to comprehend dementia praecox. And with this knowledge he was going to save his son.

With these new clues to the puzzle, Holmes worked fast. Getting the cooperation of Cook County Hospital for technical support, during the late months of 1915 he and his colleagues began to use the (then) relatively new technique of the fluoroscope to observe barium meals being passed through the digestive system. It was quickly determined that in dementia praecox patients it took 60-120 hours to pass a barium meal, but only 4-6 hours for normal controls. The barium meal tended to be stuck in the caecum and proximal colon for this abnormally long time in dementia praecox patients. A spasm of the sphincter of the colon -the 'ring of Cannon' -was blocking the passage of the meal. Holmes believed to the end of his life that this was his greatest single scientific contribution to the world, and in the article 'The relation of cecal stasis to dementia praecox' (sent to The Lancet-Clinic in April 1916 but not published until 12 August), Holmes and Retinger (1916b: 147) wrote: 'Therefore, the time necessary for the development of the toxic amines is furnished by the stay of the residue in the cecum ' [original italics]. This article confirmed identical theoretical speculations they had made in print as early as January of that year (Holmes and Retinger, 1916a).

Holmes had found the mechanisms of dementia praecox: ergot-like toxic amines produced in the caecum that poisoned many organs of the body, including the brain. The poisoning of the brain resulted in a mental disorder with psychotic symptoms. All the sufficient links in the mechanistic causal chain were present. And in Chicago some very important physicians, politicians and benefactors had noticed and were offering to help Holmes fulfil the next logical step: the establishment of a laboratory and experimental unit where new treatments or even a cure for dementia praecox could be realized. This will be described in Part 2

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