Chapter XI: Part II (6)

"It is better for women and children than for men; better for
old residents than for newcomers; worst of all for the
intemperate. According to a table of 293 carefully observed
cases given by Sternberg, the mean mortality in the whole 293
cases was 27.7 per cent. This may be taken as a fairly
representative mortality in yellow fever among the
unacclimatised, something between 25 and 30 per cent., although
in some epidemics it has risen as high as 50 or even 80 per
cent. of those attacked.... Some of these epidemic visitations
bring a heavy death-bill; thus, in New Orleans, in 1853, 7970
people died of yellow fever; in 1867, 3093; in Rio, in 1850, it
claimed 4160 victims; in 1852, 1943; and in 1886, 1397. In
Havana, the annual mortality from this cause ranges from 500 to
1600 or over."

The earlier attempts to reproduce the disease, by inoculation with its products, failed altogether:--

"In 1816, Dr. Chervin, of Point-à-Pitre (Antilles), drank
repeatedly large quantities of black vomit without feeling the
least disturbance. Some years before, other North American
colleagues, Doctors Potter, Firth, Catteral, and Parker, did
everything possible to inoculate themselves with yellow fever.
After having uselessly attempted experiments on animals, they
experimented on themselves, inoculating the black matter at the
very moment in which the moribund patient rejected it, placing
this matter in their eyes, or in wounds made in their arms,
injecting it more than twenty times in various parts of their
body ... in short, devising every sort of daring means for
experimentally transmitting yellow fever. All these experiments
were without result, and in the United States during many years
it was believed that this terrible malady was non-contagious."
(_British Medical Journal_, 3rd July, 1897.)

The history of the subject, from 1812 to 1880, is given by Dr. Finlay of Havana, in the _New York Medical Record_ (9th February 1901). In 1880, two very important reports on the disease were published; one by a Havana Commission of the National Board of Health of the United States, the other by the United States Navy Department. They tended to show that yellow fever is a "germ-disease"; that it is not wind-borne; and that there may be some change, outside the body of the patient, whereby the virulence of the active principle of the disease is heightened. From these reports, Dr. Finlay advanced his doctrine that the mosquito receives and transmits the germs of the disease:--

"It was upon the above line of reasoning (in these reports),
that I conceived the idea that the yellow-fever germ must be
conveyed from the patient to the non-immunes by inoculation, a
process which could be performed in nature only through the
agency of some stinging insect whose biological conditions must
be identical with those which were known to favour the
transmissibility of the disease."

In 1881 he inoculated himself and six soldiers with infected mosquitoes, and obtained, as he had calculated, mild attacks and subsequent immunity. During the years 1881-1900 he inoculated by this method 104 persons:--

"In these inoculations, be it remembered, my principal object
was rather to avoid than to seek the development of a severe
attack; in point of fact, only seventeen showed any appreciable
pathogenic effects after their inoculation. I felt sure,
however, that severe or fatal result might follow an inoculation
either with several mosquitoes contaminated from severe cases of
the disease, or from a single insect applied several days or
weeks after its contamination, having come to this last
conclusion in view of the facts connected with the _Anne Marie_,
and the epidemic of Saint Nazaire."

Dr. Finlay's discovery that the mosquito can convey yellow fever, and that the germ of the disease is more virulent after a prolonged sojourning in the mosquito, was proved beyond all question by the work of 1889-1901. But, so far as immunisation is concerned, few people would submit themselves to be bitten by an infected mosquito, even with perfect assurance that the germs contained in it were of a low degree of virulence: the urgent need, therefore, was for an immunising serum. In 1896, at Flores, Sanarelli discovered the _bacillus icteroides_; and by October 1897, he had prepared an immunising serum which was able to give a considerable amount of protection to animals.[40] Next year (_Annales de l'Institut Pasteur_, May 1898) came the news that he had advanced against yellow fever with its own weapons--_Premières expériences sur l'emploi du sérum curatif et préventif de la fièvre jaune_. Of the first 8 cases (Rio de Janeiro), 4 recovered. Then came the 22 cases at San Carlos do Pinhal, in Saint-Paul au Brésil (January 1898), with 16 recoveries, and only 6 deaths. And it is to be noted that he submitted his method of treatment to the utmost test that was possible; he chose the bad cases, and the country where the fever was most fatal:--

"Chaque cas était choisi de commun accord entre nous, dans le
but de mettre bien en évidence l'action thérapeutique du sérum,
_mettant toujours de côté tous les cas qui se présentaient avec
des symptômes vagues ou attenuès ou en forme légère ou fruste.
On ne conservait donc que des cas oû, d'après la violence des
phénomènes d'invasion, on devait considérer comme très peu
probable une crise spontanée de la maladie_...."

[40] It is not denied here that he made five experiments on human
beings. See Part IV. chap. ii.

Furthermore, Sanarelli was able to show the preventive value of the serum. At the end of February 1898, yellow fever broke out in the jail at San Carlos:--

"La première victime fut un condamné, qui vivait avec tous les
autres dans une salle oû les conditions hygiéniques étaient
assez mauvaises. Le lendemain, la sentinelle, qui était en
rapport continuel avec la salle des condamnés, tombait malade.
Quelques jours après, un autre condamné suivait le sort du
premier, et bientôt un quatrième cas, mortel aussi, finit par
signaler la prison comme un nouveau foyer d'infection qui venait
s'allumer au centre d'un quartier de la ville encore resté
indemne.

"Si on avait abandonné la chose à elle-même, on aurait vu se
produire le même spectacle qu'avaient fourni, dans les
conditions identiques, pendant les dernières épidémies, les
prisons de Rio-Claro, de Limeira, et d'autres villes de l'État
de Saint-Paul."

Every prisoner, except one who had already had the fever, was therefore given the preventive treatment. At once the outbreak stopped; no more cases occurred, though only a weak serum was used, though the state of the prison and its occupants was unhealthy, though the fever, two months later, was still raging round the prison, in the town.

In October 1900, the United States Commission on Yellow Fever published a preliminary report on 11 cases of mosquito-inoculation. Of these, the majority gave a negative result, and were found susceptible to infection, at a later date, from the blood of a yellow-fever patient. Two gave a positive result. In the course of these experiments, Dr. Lazear, a member of the Commission, died of the disease. In February 1901, and again in July, the Commission published further reports, emphasising the fact that the mosquito conveys the disease, and denying that the disease can be conveyed in clothing, bedding, and so forth:--

"Our observations appear to demonstrate that the parasite of
this disease must undergo a definite cycle of development in
the body of the mosquito before the latter is capable of
conveying infection. This period would seem to be not less than
twelve days.

"We also consider the question of house infection, and are able
to show that this infection is due to the presence of mosquitoes
that have previously bitten yellow-fever patients; and that the
danger of contracting the disease may be avoided in the case of
non-immune individuals who sleep in this building, by the use of
a wire screen.

"We also demonstrate, by observations made at this camp (Fort
Lazear), that clothes and bedding contaminated by contact with
yellow-fever cases, or by the excreta of these cases, is
absolutely without effect in conveying the disease."

In February 1901, Dr. H. E. Durham published an abstract of an _interim_ report of the Liverpool School Yellow Fever Commission. He and Dr. Walter Myers, the two Commissioners, had both of them been attacked by the disease, and Dr. Myers had died of it. The report gives evidence that the disease is due to a bacillus which is not the _bacillus icteroides_; and it does not wholly favour the earlier report (1900) of the American Commission. A later Commission to New Orleans, September 1901 to January 1902, reported an extensive series of investigations, which seem rather to support the belief that the _bacillus icteroides_ is the cause of the disease. Later still, this belief is again denied; and, as in rabies, so in yellow fever, the good work has gone on without waiting for the identity of this or that micro-organism.

* * * * *

Immunisation, by the direct use of an infected mosquito, may be compared with the old custom of inoculation against smallpox. The use of Sanarelli's serum-treatment has not gone far. There remains for consideration the method of keeping down infection by keeping down _Culex_.

Three reports, in 1901-1902, come from Dr. Guitéras (Havana), Surgeon-Major Gorgas, chief sanitary officer (Havana), and the Commission at New Orleans. Dr. Guitéras reports that 6 cases of yellow fever (inoculation) were treated in a large "mosquito-proof" building, which also contained cases of other diseases. No prophylaxis was enforced, save the exclusion of mosquitoes; non-immunes visited the yellow fever cases, non-immunes nursed them, and most of the attendants and labourers about the place were non-immunes; but not a single case of infection occurred. The New Orleans Commission reports that, of 200 cisterns, &c., examined in the city for the presence of larvæ, the larva of _Culex_ (_Stegomyia_) predominated in more than 60 per cent.

The report of Surgeon-Major Gorgas is very pleasant reading. For two centuries, Cuba had been cursed with yellow fever; then, after the war with Spain, America took it over:--

"The army took charge of the health department of Havana, when
deaths (from all causes) were occurring at the rate of 21,252
per year. It gives it up, with deaths occurring at the rate of
5720 per year. It took charge, with smallpox endemic for years.
It gives it up, with not a case having occurred in the city for
over eighteen months. It took charge, with yellow fever endemic
for two centuries--the relentless foe of every foreigner who
came within Havana's borders, which he could not escape, and
from whose attack he well knew every fourth man must die. The
army has stamped out this disease in its greatest stronghold."

Make fair allowance for the wide variation, from year to year, of the number of yellow fever cases in any town within the geographical belt of the disease; admit that a town may, in the course of nature, have many hundred cases in one year, and only half a dozen in another year. Again, make fair allowance for all other good influences of the American occupation of Cuba, beside those that were concerned with the stamping out of _Culex_; admit that the general death-rate of Havana, in the last February of Spanish rule (1898), was 82.32 per thousand, and in February 1901, was 19.32. Still, there is an example here, in the 1901 work in Havana, for the world to follow, wherever yellow fever exists. The following abstract of Surgeon-Major Gorgas' results was published in the _Practitioner_, May 1902, by Professor Hewlett, one of the foremost of English bacteriologists:--

"Commencing in February 1901, orders were issued that every
suspected case of yellow fever should be screened with wire
gauze at the public expense, so as to render the room or rooms
mosquito-proof. All mosquitoes in the infected house and in
contiguous houses were destroyed. After the middle of February,
100 men were employed in carrying out the destruction of the
mosquito-larvæ in their breeding places, putting oil in the
cesspools of all houses, clearing the streams, draining pools,
and oiling the larger bodies of water. Up to June, quarantine
was enforced, together with disinfection of the house and
fomites. After that, however, rigid quarantine of the patient
was stopped, and disinfection of fabrics and clothing ceased. It
was merely required that the patient should be reported, his
house placarded and screened, and a guard placed over each case
to report how general sick-room sanitation was carried out, to
see that the screen-door communicating with the screened part of
the house was kept properly closed, and to see that
communication with the sick-room was not too free, four or five
non-immunes only being allowed in. _By the end of September, the
last focus of the disease had been got rid of, and since then,
up to the beginning of January, there has not been a single
case._ Whereas, for the years since 1889, from 1st April to 1st
December, yellow fever caused an average of 410.54 deaths, with
a maximum of 1175 for 1896, and a minimum of 79 for 1899, _it
caused in 1901 5 deaths only. In the months of October and
November, when the disease has hitherto been exceedingly rife in
Havana, there has not been a single case. For the first time in
150 years, Havana has been free from yellow fever._"

Sir Patrick Manson, lecturing in America, last year, on tropical diseases, summed up the work as follows:--

"Time will not permit--what to you is probably quite
unnecessary--the recapitulation of the story of the labours of
Reed and his coadjutors. I cannot pass on, however, to what I
have to say in connection with this work without a word of
admiration for the insight, the energy, the skill, the courage,
and withal the modesty and simplicity of the leader of that
remarkable band of workers. If any man deserved a monument to
his memory, it was Reed. If any band of men deserve recognition
at the hands of their countrymen, it is Reed's colleagues.

"The principal outcome of the labours of these men has been the
demonstration, first, that the ultra-microscopic germ of yellow
fever is present in the blood of the patient during the first
three days of the disease. Second, that the first step in the
passage of the germ from the sick to the sound is made, under
natural conditions, in the stegomyia mosquito. And third, that
after about twelve days and upwards in stegomyia, the yellow
fever germ, when implanted by the said mosquito into another
human host, is capable of reproduction, so that at the end of a
further period of about three days it has established itself
throughout the blood, is causing the violent reaction, the
clinical manifestations of which we call yellow fever, and is
once more in a condition to re-enter the mosquito.

"These are great etiological facts. They are of supreme
practical and scientific value. Acting on them, the United
States sanitary authorities expelled yellow fever from Havana.
Acting on them, they should be able in the future to protect the
United States themselves from such terrible visitations as in
the past have swept through some of your cities."

3. FILARIASIS

These same lectures contain an admirable account of the life-history of _Filaria_. It is not necessary here to describe the loathsome deformities which occur in the later stages of filariasis. These deformities (_elephantiasis_, Barbadoes leg), which may attain colossal size, are due to the blocking of the lymphatic vessels with filarial worms. Cases of the disease are hardly ever seen in this country; but it is very frequent in some parts of the tropics. _In the endemic areas_, says Manson, _10 per cent. is not an uncommon proportion of the population to be found affected with filariasis. Thirty and even 50 per cent. may be affected. In many of the Pacific Islands--the Samoa group for instance--I believe that even this proportion is exceeded._

That _Culex_ (_fatigans_) can carry the parasite, has been proved past all doubt. Neither does anybody doubt, that the keeping down of this mosquito would keep down filariasis. A report of great interest, from Barbadoes, was published in the _British Medical Journal_ for 14th June 1902. It is written by Dr. Low, whose experiment on himself in the Campagna has already been noted in this chapter. Dr. Low reports that there is no indigenous malaria in the island, and that neither he nor Mr. Lefroy could find a single _Anopheles_ larva, though they hunted diligently in the swamps and other likely places. But filariasis is terribly common, and so is _Culex fatigans_. Dr. Low examined the night-blood of 600 cases of all kinds in the General Hospital, the Central Almshouse, and elsewhere, and found the filaria-embryos in no less than 76 = 12.66 per cent. He caught and dissected a hundred mosquitoes (_Culex fatigans_) from the wards and corridors of the General Hospital, and found that no less than 23 of them were infected. If it were not for _Culex_, and for men's indifference and apathy, filariasis could be kept down all over the island:--

"There is a perfect water supply, and people can get their water
fresh from the standpipes at their doors. Old wells ought to be
filled up; no water-barrels or tubs should be allowed, or, if
kept, they should be emptied every week or so. Tanks and
collections of water in gardens should all be periodically
treated with kerosene, or be furnished with closely-fitting
covers to prevent mosquitoes getting in. These methods are
simple and inexpensive, and each householder should see that
they are applied in his garden and grounds. The difficulty
begins when one has to take into account the inability of the
negro to grasp anything of a hygienic nature. The only way to
get over this, would be a system of sanitary inspection by a few
competent men. For individual prophylaxis, mosquito-nets ought
always to be used; but many, even educated people, still persist
in sleeping without them; of course, nothing in this line can be
expected of the native population.

"If such means were adopted for Barbadoes, the presence of
filarial disease, which at present is quite alarming, could
easily, with little trouble and expense, be greatly diminished,
and thus save much suffering, as well as loss of time, hideous
deformity, and doubtless in not a few instances loss of life."

Thus, in a few years, from experiments on mosquitoes, sparrows, and men, has come the present plan of campaign against malaria, yellow fever, and filariasis; that is, against _Anopheles_ and _Culex_. He who would know what is being done to check these diseases in Italy, India, China, Africa, and America, must read Prof. Ross' _Malarial Fever, its Cause, Prevention, and Treatment_ (1902), and _Mosquito Brigades, and how to organise them_ (1902). There has been nothing like it since Pasteur died. Far and wide, from Staten Island to Cuba, from Hong Kong to Lagos, the work of keeping down the larvæ of _Anopheles_ and _Culex_ is going on. _Henceforth we have to reckon not with a nameless something, but with a definite parasite, whose conditions of life are known. Before all things, we must shut off the sources of the infection._ For centuries, men had believed in exhalations and miasmata lying all over the land: and, behold, the agents of malaria are in the puddles round a man's house, and the agents of yellow fever are in the water-butt and the broken bottles and old sardine-tins. Science has given the word, and now there are _Anopheles_ brigades and _Culex_ brigades set going; labourers with brooms and rubbish-carts, sweeping out the stagnant pools, draining the surface soil, and carrying off the odd receptacles that serve to hold mosquito eggs and larvæ. The job, like all sanitary jobs, must be steady, year in, year out: it must be limited to infected places, a whole continent cannot be treated. But there the work is, and will grow; and saves, by unskilled labour, and at a trivial expense, those "non-acclimatised" lives that have hitherto been thrown away as recklessly as the larvæ that are now swept out of the puddles and ditches round African settlements.

XI

PARASITIC DISEASES

The foregoing chapters are concerned with bacteriology alone, and with those curative or preventive methods of treatment that have come out of inoculation-experiments on animals. The lives that are saved, or safeguarded, by these methods, even in one year, must be many thousands in each country of the civilised world. And, beside human lives, there is the protection of sheep and cattle against anthrax, swine against rouget, horses against tetanus, cattle against rinderpest. In Cape Colony alone, so far back as 1899, about half a million cattle had received preventive treatment against rinderpest; and the sum total of human and animal lives saved or safeguarded, in all parts of the world, must be reckoned in millions by this time.

The present chapter, and the next two chapters, are concerned with methods that have come out of experiments on animals, but not out of bacteriology.

It is plain that the grosser parasites of the human body, tapeworms and the like, could not be explained or understood without the help of feeding-experiments on animals. By this method, and by this alone, their life-history was discovered. They were known to Aristotle and to Hippocrates; but nothing was understood about them. They were never studied, for this among other reasons, that men believed in spontaneous generation; and the presence of lower forms of life inside human bodies was attributed to the fault of the patient, or the work of the devil. Then, at last, Redi (1712), and Swammerdam (1752) in his _Bibel der Natur_, struck at the doctrine of spontaneous generation, saying that it did not apply to insects; and in 1781 Pallas boldly declared that the internal parasites of man came out of eggs, like insects, and not "of themselves." It would be a good theme for an essay--_The paralysing effect, on medicine and surgery, of the doctrine of spontaneous generation_. Rudolphi (1808) and Bremser (1819) opposed Pallas; and von Siebold (1835) and Eschricht (1837) supported him. Then came the great students of this part of biology--Cobbold, Busk, Davaine, van Beneden, Leuckart, Küchenmeister. In 1842, Steenstrup had discovered, in certain insects, the alternation of generations; in 1852, Küchenmeister proved that the generations of internal parasites are similarly alternate. By feeding carnivorous animals with "measly" meat, he produced tapeworms in them; and by feeding herbivorous animals with the ova of tapeworms, he made their muscles "measly."

The feeding of animals was the only possible way to understand the bewildering transformations and transmigrations of the thirty or more entozoa to which flesh is heir. This chapter of pathology makes up in tragedy what it lacks in romance; for these animal parasites have killed whole hosts of people. Take, for instance, the _trichina spiralis_, a minute worm discovered in 1835 encysted in countless numbers in the muscles of the human body; it was studied by Virchow, Leuckart, and others, by feeding-experiments on animals, and was proved to come from infected half-cooked ham and pork, and to make its way from the alimentary canal all over the body. The name of trichiniasis or trichina-fever was given to the acute illness that came of the sudden dissemination of these myriad parasites into the tissues. Trichiniasis had killed hundreds of people by a most painful death; outbreaks of it, in Germany and elsewhere, had swept through villages like cholera or plague: then Leuckart and Virchow traced it to its source, and it was stopped there--_Above all things, we must shut off the sources of the infection_--the butchers' shops were kept under sanitary inspection, people were warned against half-cooked ham and pork, and there was an end of it.

Or take hydatid disease, which occurs in all parts of the world, and in some countries (Australia, Iceland) is terribly common. The nature of this disease--that it is an animal parasite transmissible between men and dogs--was proved by feeding-experiments on animals. In Iceland, where men and dogs live crowded together in huts, there is an appalling number of deaths from hydatid disease; Leuckart, in 1863, of it:--

"At present, almost the sixth part of all the inhabitants
annually dying in Iceland fall victims to the echinococcus
epidemic."

Before Küchenmeister's experiments in 1852, there was no general knowledge of the exact pathology of entozoic disease. The advance was not made by the experimental method alone; other things helped: but among them was neither clinical experience, nor what Sir Charles Bell called "the observation of the just facts of anatomy and of natural motions."

* * * * *

Beside the entozoa, there are also vegetable parasites. Of these, the most important is the _streptothrix actinomyces_, the cause of actinomycosis in man and cattle. Israel, in 1877, gave the first accurate account of it in man; and Böllinger, the same year, studied it in cattle. Ponfick, in 1882, recognised the identity of the disease in man and animals. In 1885, Israel published the collected records of 37 cases in man, tabulated according to the site of the primary infection. Boström, about this time, made cultures of the fungus: but all the earlier attempts at inoculation failed; and it was not till 1891 that Wolff and Israel published their successful inoculations, and thus completed the evidence that actinomycosis is a parasitic infection, a growth of vegetable threads and spores, transmissible between men and animals, and able to keep its vitality outside its host; so that men who are employed with cattle, or have the habit of chewing straws or ears of corn, incur some slight risk of infection. Before 1877, the disease was hardly suspected in man, and was not understood in cattle.

XII

MYXOEDEMA

On 4th October 1873, Sir William Gull read a short paper before the Clinical Society of London, "On a Cretinoid State supervening in Adult Life in Women." This famous first account of myxoedema was based on five cases: it is less than five pages long, it does not suggest a name for the disease, and it says nothing about the thyroid gland. Four years later (23rd October 1877), Dr. Ord read a paper before the Medico-Chirurgical Society of London, "On Myxoedema; a term proposed to be applied to an essential condition in the 'Cretinoid' Affection occasionally observed in Middle-aged Women." His work had begun so far back as 1861; and in this 1877 paper he gave not only clinical observations, but also pathological and chemical facts; and he noted, as one among many changes, wasting of the thyroid gland. He also pointed out the close resemblance between cases of myxoedema and cases of sporadic cretinism.

In 1882, Reverdin stated before the Medical Society of Geneva that signs like those of myxoedema had been observed in some cases of removal of the thyroid gland on account of disease (goître). In April 1883, Kocher of Berne read a paper on this subject, before the Congress of German Surgeons; but he attributed this myxoedema after removal of the gland (cachexia strumipriva) not directly to the loss of thyroid-tissue, but rather to some sort of interference with free respiration, due to operation. On 23rd November, Sir Felix Semon brought the subject again before the Clinical Society; and on 14th December 1883, the Society appointed a Committee of Investigation to study the whole question.

Their report, 215 pages long, with tabulated records of 119 cases of myxoedema, was published in 1888. It is a monument of good work, historical, clinical, pathological, chemical, and experimental. Twenty years ago, the purpose of the thyroid gland was unknown: a few experiments had been made on it, by Sir Astley Cooper and others, and had failed; and Claude Bernard, in his _Physiologie Opératoire_ (published in 1879, soon after his death), makes it clear that nothing was known in his time about it. He is emphasising the fact that anatomy cannot make the discoveries of physiology:--

"The descriptive anatomy, and the microscopic characters, of the
thyroid gland, the facts about its blood-vessels and its
lymphatics--are not all these as well known in the thyroid gland
as in other organs? Is not the same thing true of the thymus
gland, and the suprarenal capsules? _Yet we know absolutely
nothing about the functions of these organs--we have not so much
as an idea what use and importance they may possess--because
experiments have told us nothing about them_; and anatomy, left
to itself, is absolutely silent on the subject."

Therefore, in 1882-83, things stood at this point--that the removal of a diseased thyroid gland had been followed, in some cases, by a train of symptoms such as Sir William Gull had recorded in 1873. Would the same symptoms follow removal of the healthy gland? The answer was given by Sir Victor Horsley's experiments, begun in 1884. He was able, by removal of the gland, to produce in monkeys a chronic myxoedema, a cretinoid state, the facsimile of the disease in man: the same symptoms, course, tissue-changes, the same physical and mental hebetude, the same alterations of the excretions, the temperature, and the voice. It was now past doubt that myxoedema was due to want of thyroid-tissue, and to that alone; and that "cachexia strumipriva" was due to the loss, by operation, of such remnants of the gland as had not been rendered useless by disease.

The advance had still to be made from pathology to treatment. Here, so far as England is concerned, honour is again due to Sir Victor Horsley. On 8th February 1890, he published the suggestion that thyroid-tissue, from an animal just killed, should be transplanted beneath the skin of a myxoedematous patient:--

"The justification of this procedure rested on the remarkable
experiments of Schiff and von Eisselsberg. I only became aware
in April 1890, that this proposal had been in fact forestalled
in 1889 by Dr. Bircher, in Aarau. (The date of Dr. Bircher's
operation was 16th January 1889.) Kocher had tried to do the
same thing in 1883, but the graft was soon absorbed; but early
in 1889 he tried it again, in five cases, and one greatly
improved."

The importance of this treatment, by transplantation of living thyroid-tissue, must be judged by the fact that in 1888 no practical use had yet been made of the scientific work that had been done. The Clinical Society's Report, published that year, gives but half a page to treatment, of the old-fashioned sort; and not a word of hope.

Then, at last, in 1891, came Dr. George Murray's paper in the _British Medical Journal_, "Note on the Treatment of Myxoedema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep." Later, hypodermic injections of thyroid-extract gave way to sandwiches, made with thyroid gland (Dr. Hector Mackenzie, and Dr. Fox of Plymouth), and these in their turn were eclipsed by tabloids.

It is a strange sequence, from 1873 onward: clinical observation, _post-mortem_ work, calamities of surgery, experimental physiology, transplantation, hypodermic injections, sandwiches, and tabloids. And far more has been achieved than the cure of myxoedema. Even if the discovery stopped here, it would still be a miracle that little bottles of tabloids should bring men and women back from myxoedema to what they were before they became thick-witted, slow, changed almost past recognition, drifting toward idiocy. But it does not stop here. The same treatment has given good results in countless cases of sporadic cretinism, restoring growth of body and of mind to children that were hopelessly imbecile. It is of great value also for certain diseases of the skin. Moreover, physiology has gained knowledge of the purpose of the thyroid gland, and a clearer insight into the facts relating to internal secretion.

XIII

THE ACTION OF DRUGS

Long after the Renaissance, the practice of medicine was still under the influence of magic. Whatever things were rare and precious were held to be good against disease--gold, amber, coral, pearls, and the dust of mummies; whatever took strange forms of life--toads, earthworms, and the like; whatever looked like the disease, after the doctrine of signatures--pulmonaria for the lungs, because the spots on its leaves were like tubercle, a kidney-shaped fruit for the kidneys, a heart-shaped fruit for the heart, and yellow carrots for the yellow jaundice. Among the drugs in the 1618 Pharmacopoeia are _cranium humanum_, _mandibula lucii_, _nidus hirundinum_, _sericum crudum_, _linum vivum_, and _pilus salamandræ_. In the Pharmacopoeia of 1667 are _exuviæ serpentis_, _telæ aranearum_, _saliva jejuni_, _cranium hominis violentâ morte extincti_, and worse obscenities.

Soon after the publication of this Pharmacopoeia, on 14th February 1685, King Charles II. died; and in the Library of the Society of Antiquaries there is a manuscript account in Latin, by Dr. Scarbrugh, how the case was treated. The King had sixteen physicians, and nine consultations in five days; and to say "everything was done that was possible" gives no idea of the vigour of the treatment. Finally, the day he died, they gave him, eleven of them in consultation--_totus medicorum chorus ab omni spe destitutus_--they gave him, as _more generous cardiacs_, the _lapis Goæ_, and the _Bezoar-stone_. The _lapis Goæ_ was a dust of topaz, jacinth, sapphire, ruby, pearl, emerald, bezoar, coral, musk, ambergris, and gold, all made into a pill and polished; and the _bezoar_ is a calculus found in the intestines of herbivorous animals. Half a century later, the Pharmacopoeia of 1721 still included ants' eggs, teeth, _lapis nephriticus_, and other horrors; and in the Pharmacopoeia of 1746, though the dust of Egyptian mummies was ruled out, vipers and wood-lice were retained.

Certainly these "last enchantments of the Middle Ages" were slow to depart. Clinical observation, anatomy, and pathology, had all failed to bring about a right understanding of the actions of drugs. It was the physiologists, not the doctors, who first formulated the exact use of drugs; it was Bichat, Magendie, and Claude Bernard. That is the whole meaning of Magendie's work on the upas-poison and on strychnine, and Claude Bernard's work on curari and digitalis. Of these four substances, two only are of any use in practice; yet Magendie's study of strychnine[41] was of immeasurable value, not so much because it gave the doctors a "more generous cardiac," though that was a great gift, but because it revealed the _selective_ action of drugs. Contrast his account of strychnine with Ambroise Paré's story how they tested the bezoar-stone on the thief instead of hanging him; contrast Bernard's chapter on curari with Dr. Scarbrugh's notes on the King's death, with all the Crown jewels inside him: you are in two different worlds. The _selective_ action of drugs--the affinity between strychnine and the central nerve-cells, between curari and the terminal filaments of the motor nerves--that was the revolutionary teaching of science: and it came, not by experience, but by experiment.

[41] For a full statement of the great value of this study of
strychnine, see Cl. Bernard, _Leçons de Physiologie Opératoire_,
1879, p. 89.

Take Professor Fraser's address on "The Action of Remedies, and the Experimental Method" at the International Medical Congress in London, 1881:--

"The introduction of this method is due to Bichat; and, by its
subsequent application by Magendie, pharmacology was originated
as the science we now recognise. Bichat represents a transition
state, in which metaphysical conceptions were mingled with the
results of experience. Magendie more clearly recognised the
danger of adopting theories, in the existing imperfections of
knowledge; and devoted himself to the supplementing of these
imperfections by experiments on living animals. The advantages
of such experiments he early illustrated by his investigation on
the upas-poison; and afterwards by a research on the then
newly-discovered alkaloid, strychnia.... He demonstrated the
action of this substance upon the spinal cord, by experiments
upon the lower animals, so thoroughly, that subsequent
investigations have added but little to his results."

Or take Professor Fraser's account of digitalis:--

"It was introduced as a remedy for dropsy; and, on the
applications which were made of it for the treatment of that
disease, a slowing action upon the cardiac movements was
observed, which led to its acquiring the reputation of a cardiac
sedative. Numerous observations were made on man by the
originators of its application, by Dr. Sanders and many other
physicians, in which special attention was paid to its effects
upon the circulation; but no further light was thrown upon its
remarkable properties, with the unimportant exception that in
some cases it was found to excite the circulation. It was not
until the experimental method was applied in its investigation,
in the first instance by Claude Bernard, and subsequently by
Dybkowsky, Pelikan, Meyer, Boehm, and Schmiedeberg, that the
true action of digitalis upon the circulation was discovered. It
was shown that the effects upon the circulation were not in any
exact sense sedative, but, on the contrary, stimulant and tonic,
rendering the action of the heart more powerful, and increasing
the tension in the blood-vessels. The indications for its use in
disease were thereby revolutionised, and at the same time
rendered more exact; and the striking benefits which are now
afforded by the use of this substance in most (cardiac) diseases
were made available to humanity."

Or take Sir T. Lauder Brunton's account of the action of nitrite of amyl in angina pectoris:--

"The action of nitrite of amyl in causing flushing was first
observed by Guthrie, and Sir B. W. Richardson recommended it as
a remedy in spasmodic conditions, from the power he thought it
to possess of paralysing motor nerves. In the spring of 1867 I
had opportunities of constantly observing a patient who suffered
from angina pectoris, and of obtaining from him numerous
sphygmographic tracings, both during the attack and during the
interval. These showed that during the attack the pulse became
quicker, the blood-pressure rose, and the arterioles
contracted.... It seemed probable that the great rise in tension
was the cause of the pain, and it occurred to me that if it was
possible to diminish the tension by drugs instead of by
bleeding, the pain would be removed.

"I knew from unpublished experiments on animals by Dr. A. Gamgee
that nitrite of amyl had this power, and therefore tried it on
the patient. My expectations were perfectly answered. The pain
usually disappeared in three-quarters of a minute after the
inhalation began, and at the same time the pulse became slower
and much fuller, and the tension diminished."

Of course it would be easy to lengthen out the list. Aconite, adrenalin, belladonna, calcium chloride, colchicum, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics--all these drugs, and many more, have been studied and learned by experiments on animals. Then comes the answer, that drugs act differently on animals and on men. The few instances, that give a wise air to this foolish answer, were known long ago to everybody: they do not so much as touch the facts of daily practice:--

"The action of drugs on man differs from that on the lower
animals chiefly in respect to the brain, which is so much more
greatly developed in man. Where the structure of an organ or
tissue is nearly the same in man and in the lower animals, the
action of drugs upon it is similar. Thus we find that carbonic
oxide, and nitrites, produce similar changes in the blood of
frogs, dogs, and man, that curare paralyses the motor nerves,
alike in them all, and veratria exerts upon the muscles of each
its peculiar stimulant and paralysing action. Where differences
exist in the structure of the various organs, we find, as we
would naturally expect, differences in their reaction to drugs.
Thus the heart of the frog is simpler than that of dogs or men,
and less affected by the central nervous system; we consequently
find that while such a drug as digitalis has a somewhat similar
action upon the hearts of frogs, dogs, and men, there are
certain differences between its effect upon the heart of a frog
and on that of mammals.

"Belladonna offers another example of apparent difference in
action--a considerable dose of belladonna will produce almost no
apparent effect upon a rabbit, while a smaller dose in a dog or
a man would cause the rapidity of the pulse to be nearly
doubled. Yet in all three--rabbits, dogs, and men--belladonna
paralyses the power of the vagus over the heart. The difference
is that in rabbits the vagus normally exerts but little action
on the heart, and the effect of its paralysis is consequently
slight or hardly appreciable." (Professor Fraser.)

It would be strange indeed, if experts who work in micromillimetres and decimal milligrammes, and study the vanishing-point of microscopic structures, and measure and ordain infinitesimal changes in invisible organisms, were blind to such gross and palpable differences as exist between men and pigeons in their susceptibility to a dose of opium.

Anæsthetics must be reckoned among the drugs that have been studied on animals: but, for the discovery of them, men experimented on themselves. The first use of nitrous oxide (laughing gas) in surgery was 11th December 1844, when Horace Wells, of Connecticut, had it administered to himself for the removal of a tooth. The first use of ether was made by Dr. Long, of Athens, Georgia; but he did not publish the case, or follow up the work: and the honour of the discovery of ether went to Morton, of Boston, who made repeated experiments, both on animals and on himself. The date when he first rendered himself absolutely unconscious for seven or eight minutes, is 30th September 1846; and the first operation under ether was done on 16th October, in the Massachusetts General Hospital. The first use of chloroform was 4th November 1847, that famous evening when Simpson, George Keith, and Matthews Duncan took it together. The whole history of anæsthesia is to be found in the _Practitioner_, Oct. 1896.

It is sometimes said that the men who make experiments on animals ought to make them on themselves. But they do, hundreds of them, and suffer for it: Heaven knows the list is long enough--the discoverers of anæsthesia, Hunter, Garré, Koch, Klein, Moor, Haffkine, Grassi, Bochefontaine, Quesada, Sanarelli, Pettenkofer--these and hosts more, here or abroad, have done it, as part of the day's work; and some--by accidental infection, like Chabry and Villa, or by deliberate self-inoculation, like Carrion--have been killed:--

"Dr. Angelo Knorr, _Privat-docent_ in the Veterinary School of
Munich, died on 22nd February from acute glanders, contracted in
the course of an experimental research on mallein. Helmann, the
Russian investigator who discovered mallein, himself fell a
victim to accidental inoculation of the glanders virus. Some
time afterwards another Russian, Protopopow, died of glanders
contracted in a French laboratory. An Austrian physician, Dr.
Koffman-Wellenhof, died of the same disease, contracted in the
Institute of Hygiene at Vienna. On 17th January of the present
year Dr. Guiseppe Bosso, of the University of Turin, died of
infection contracted in the course of cultivations of
tubercle-bacilli made in his laboratory. Not long before, Dr
Lola, assistant in the maternity department of the Czech
University Hospital of Prague, died of tetanus caused by an
experimental inoculation made on himself. Some fourteen or
fifteen years ago, a medical student of Lima proved that
'verruga Peruana' is an infectious disease by inoculating
himself with it, an act of scientific devotion which cost him
his life.[42] Besides those who have died, there are many who
have only escaped with their lives after long and painful
illness. Professor Kourloff contracted anthrax in a laboratory
at Munich, and was saved only by vigorous surgery. Dr. Nicolas
supplied, in his own person, the first example of tetanus
produced in man by inoculation of the pure toxin of the
bacillus of Nicolaier." (_Brit. Med. Journal_, 18th March 1899.)

[42] Daniel Carrion, born 1859 at Cerro de Pasco, proved, by
self-inoculation, the identity of the two forms of the disease,
27th August 1885; died of the disease, 5th October. See _Ann. de
l'Inst. Past._, Sept 1898.

This list is seven years old now; it is twice the length by this time. Typhoid, malaria, yellow fever, have all taken toll of those who study them. It is a long record of the men who fell ill, or died, or killed themselves over their work; and the deaths of Barisch, Dr. Müller, and Nurse Pecha, from plague at Vienna (October 1898) are another instance that there is danger in the constant handling of cultures. But these deaths at Vienna were due to the great carelessness of one man. In laboratories in all parts of the world there are stored cultures of all sorts of organisms, yet no harm comes of it. "More cases of infection occur amongst young medical men attending fever cases, whether in private practice or hospital wards, in a single month, than have occurred in the whole of the laboratories in the world since they were established." (_British Medical Journal_, 29th October 1898.) Outside the laboratory, outside the fever hospitals, the risk is something less than a negligible quantity:--

"Apart from plague and cholera, in all the big laboratories
studies are uninterruptedly pursued, from one end of the year to
the other, upon anthrax, glanders, influenza, Malta fever,
various tropical diseases which do not exist at all or are rare
in the countries where they are being studied. The laboratories
in question are situated in the largest and most important towns
of their respective countries; and, within those towns, very
often in the most fashionable or most populous centres.... On no
occasion was there even a suspicion aroused of an epidemic
having been produced by any of the above-mentioned institutes,
or by those tens of thousands of operations against cholera
performed in India." (Haffkine, _Madras Mail_, 8th December
1898.)

XIV

SNAKE-VENOM

The Report of the 1875 Commission said:--

"It is not possible for us to recommend that the Indian
Government should be prohibited from pursuing its endeavours to
discover an antidote for snake-bites; or that, without such an
effort, your Majesty's Indian subjects should be left to perish
in large numbers annually from the effects of these poisons."

Certainly it was not possible; and the numbers are large indeed. During 1897, 4227 persons were killed by wild animals in India, and 20,959 by snakes. (_British Medical Journal_, 5th November 1898.)

Sir Joseph Fayrer's name must be put in the highest place of all those who have studied the venomous snakes of India.

Sewell, in 1887, showed that animals could be rendered immune, by repeated inoculation with minute quantities of rattlesnake-venom, to a dose seven times as large as would kill an unprotected animal. Kanthack, in 1891, immunised animals in the same way against cobra-venom. He also made experiments to ascertain whether the blood-serum of these animals acted as an antidote to the venom. Then came the work of Calmette, Fraser, Phisalix, Bertrand, Martin (Australia), Stephens, and Meyers. Professor Fraser's observations on the antidotal properties of the bile are, of course, of the utmost importance; not only in preventive medicine, but also in physiology. The results obtained by Calmette are a good instance of the fineness and accuracy of the experimental method. It is to be noted that the animals were inoculated with a fine needle, not thrust into cages with snakes, as at zoological gardens; and that an animal thus poisoned has a painless death. The different venoms were measured in decimal milligrammes, and their potency was estimated according to the body-weight of the animal inoculated. As with tetanus, so with snake-venom, there must be a standard, or "unit of toxicity."

"The following table gives the relative toxicity, for 1 kilogr.
of rabbit, of the different venoms that I have tested. To denote
this toxicity I use terms such as Behring, Roux, and Vaillard
used for the toxin of tetanus, taking the number of grammes of
animal killed by one gramme of toxin:--

1. Venom of _naja_ 0.25 mgr. per kilogr. of rabbit.

One gramme of this venom kills 4000 kilogrammes of
rabbit; it has, therefore, an activity of 4,000,000

2. Venom of _hoplocephalus_ 0.29 mgr 3,450,000

3. Venom of _pseudechis_ 1.25 mgr 800,000

4. Venom of _pelias berus_ 4.00 mgr 250,000

"Of course, this estimation of virulence is not absolute; it
varies considerably according to the species of animal tested.
Thus the guinea-pig, and still more the rat, are extremely
sensitive. For instance, 0.15 mgr. of viper-venom is enough to
kill, in less than 12 hours, 500 grammes of guinea-pig; so that
the activity of this venom with a guinea-pig is 3,333,000, but
with a rabbit is not more than 650,000. With more resistant
animals, the opposite result is obtained; about 10 mgr. of
cobra-venom are necessary to kill a dog of 6.50 kilogrm. weight;
but to kill the same weight of rabbit 1.65 mgr. is enough. Thus
the virulence of this venom with the rabbit is 4,000,000; but
with the dog not more than 650,000."

By experiments in test-tubes, Calmette studied these venoms under the influences of heat and various chemical agents. He found how to attenuate their virulence, and how to diminish the local inflammation round the point of inoculation; and it was in the course of these test-tube experiments and inoculations that he discovered the value of calcium hypochlorite as a local application. Working, by various methods, with attenuated venoms, he was able to immunise animals:--

"I have come to immunise rabbits against quantities of venom
that are truly colossal. I have got several, vaccinated more
than a year ago, which take, without the least discomfort, so
much as 40 mgr. of venom of _naja tripudians_ at a single
injection; that is to say, enough to kill 80 rabbits of 2
kilogr. weight, or 5 dogs.

"Five drops of serum from these rabbits wholly neutralise _in
vitro_ (in a glass test-tube) the toxicity of 1 mgr. of
_naja_-venom."

By 1894 he had found that the serum of an animal, thus immunised by graduated doses of one kind of venom, neutralised other kinds of venom:--

"If 1 mgr. of cobra-venom, or 4 mgr. of viper-venom, be mixed,
in a test-tube, with a small quantity of serum from an immunised
rabbit, and a fresh rabbit be inoculated with this mixture, it
does not suffer any discomfort. It is not even necessary that
the serum should come from an animal vaccinated against the same
sort of venom as that in the mixture. _The serum of a rabbit
immunised against the venom of the cobra or the viper acts
indifferently on all the venoms that I have tested._"

In 1894 he had prepared enough serum for the treatment to be tried by his own countrymen practising in some of the French colonies. In April 1895, he gave the following account of his work:--

"I have immunised two asses, one having received 220 mgr. of
_naja_-venom from 25th September to 31st December 1894, and the
other 160 mgr. from 15th October to 31st December. The serum of
the first of these two animals has now reached this point, that
half a cubic centimetre destroys the toxicity of 1 mgr. of
_naja_-venom. Four cubic centimetres of this serum, injected
four hours before the inoculation of a dose of venom enough to
kill twice over, preserve the animal in every case. It is also
therapeutic, under the conditions that I have already defined;
that is to say, if you first inoculate a rabbit with such a dose
of venom as kills the control-animals in three hours, and then,
an hour after injecting the venom, inject under the skin of the
abdomen 4 to 5 cubic centimetres of serum, recovery is the rule.
When you interfere later than this the results are uncertain;
and in all my experiments the delay of an hour and a half is the
most that I have been able to reach.

"This antivenomous serum of asses has these same antitoxic
properties with all kinds of snake-venom; it is equally active
_in vitro_, preventive, and therapeutic, with the venoms of
_cerastes_, of _trigonocephalus_, of _crotalus_, and of four
kinds of Australian snakes that Mr. MacGarvie Smith has sent to
M. Roux. I am still injecting these two animals with venom, and
I hope to give to their serum at last a much greater antitoxic
power."

In 1896 four successful cases of this treatment in the human subject were reported in the _British Medical Journal_. In 1898 Calmette made the following statement of his results:--

"It is now nearly two years since the use of my antivenomous
serum was introduced in India, in Algeria, in Egypt, on the West
Coast of Africa, in America, in the West Indies, Antilles, &c.
It has been very often used for men and domestic animals (dogs,
horses, oxen), and up to now none of those that have received an
injection of serum have succumbed.... A great number of
observations have been communicated to me, and not one of them
refers to a case of failure." (_British Medical Journal_, 14th
May 1898.)