"The annual admissions _per mille_ for e_Experiments on Animals

British troops in India have risen from 18.5 in 1890 to 32.4 in

1897, while the death-rate has increased from 4.01 to 9.01; and

we are of opinion that every practicable means should be tried

to guard against the ravages made by this disease. The

anti-typhoid inoculations have been, we believe, on a

sufficiently large scale to show the actual value of the

treatment, while the results appear to afford satisfactory proof

that the inoculations, when properly carried out, afford an

immunity equal to or greater than that obtained by a person who

has undergone an attack of the disease; further, the operation

is one which does not cause any risk to health. In these

circumstances, we are very strongly of opinion that a more

extended trial should be made of the treatment; and we trust

that your Lordship will permit us to approve the inoculation, at

the public expense, of all British officers and soldiers who may

voluntarily submit themselves to the operation."

On 1st August, the Secretary of State for India announced in

Parliament that this treatment, at the public expense, had been

sanctioned.

On 20th January 1900, Professor Wright published in the _British

Medical Journal_ an account of these 1898-99 inoculations in India.

"They were undertaken under conditions which were very far from ideal.

In particular, there is reason to suppose that the results obtained

may have been unfavourably influenced by a weakening of the vaccine,

brought about by repeated re-sterilisation." In no case was

reinoculation done. The statistics were compiled from information

furnished by officers of the Royal Army Medical Corps actually in

charge of troops in the various stations; and were supplemented by

reports received from the commanding officers of the various

inoculated regiments. They are as follows:--

+------------------+------+-------+----------+----------+

+------------------+------+-------+----------+----------+

|Inoculated 2835| 27 | 5 | 0.95 | 0.2 |

|Uninoculated 8460| 213 | 23 | 2.5 | 0.34 |

+------------------+------+-------+----------+----------+

If the inoculated had been attacked equally with the uninoculated

throughout the period of observation, they would have had 71 cases

instead of 27.

These inoculations belong to the early part of 1899. During the rest

of the year, inoculations were made in India, Egypt, and Malta: the

results are given in an appendix to the Report of the Royal Army

Medical Department, 1899. (See _British Medical Journal_, 21st

September 1901.) The great majority of the troops tabulated were in

India. Of the troops stationed at Malta, 61 were inoculated, 2456 not

inoculated; among the former there were no cases, among the latter

there were 17 cases and 5 deaths. In Egypt, of 4835 troops, 461 were

inoculated; among these there were no cases, among the uninoculated

there were 30 cases and 7 deaths. In India, of 30,353 troops, 4502

were inoculated, leaving 25,851 not inoculated; among the inoculated

there were 44 cases and 9 deaths, among the non-inoculated 657 cases

and 146 deaths. Taking the Indian statistics, and estimating

percentage to strength, we find, amongst the inoculated, admissions

0.98, deaths 0.2; amongst the non-inoculated, admissions 2.5, deaths

0.56. The cases which occurred amongst the inoculated men were in the

majority of instances of a mild character. Taking Malta, Egypt, and

India together, it appears that the inoculated, if they had suffered

equally with the non-inoculated, would have had 108 cases and 24

deaths, instead of 44 cases and 9 deaths.

At the end of 1899, this treatment, only just out of the hands of

science, was suddenly demanded for the protection of a huge army at

war in a country saturated with typhoid. Still, the South African

results, and other results during 1899 to 1901, show a good balance of

lives saved. The following paragraphs give all results published from

the beginning of 1900 to May 1902. They are put in order of

publication. Doubtless a few other reports have been overlooked in

compilation; but the list includes all that were easily accessible.

1. _Manchester, England._ The _British Medical Journal_, 28th April

1900, contains a note by Dr. Marsden, Medical Superintendent of the

Monsall Fever Hospital, Manchester, on the inoculation of 14 out of 22

nurses engaged in nursing typhoid patients. Of the remaining 8, 4 had

already had typhoid. The inoculations were made in October 1899. The

following table shows the subsequent freedom from typhoid of the

nursing staff:--

+-------------------------------+-----------------+--------------+

| Year. | Number of | Cases among |

| |Typhoid Patients.|Nursing Staff.|

+-------------------------------+-----------------+--------------+

| 1895 | 229 | 3 |

| 1896 | 238 | 3 |

| 1897 | 302 | 4 |

| 1898 | 426 | 8 |

| To end of September 1899 | 163 | 5 |

|From October 1899 to March 1900| 146 | 0 |

+-------------------------------+-----------------+--------------+

2. _Ladysmith, South Africa._ The _Lancet_, 14th July 1900, contains a

short note by Professor Wright, on the distribution of typhoid among

the officers and men of the military garrison, during the siege of

Ladysmith. The figures are as follows:--

+-------------+-------+------+----------+-------+----------+----------+

+-------------+-------+------+----------+-------+----------+----------+

|Not | | | | | | |

| inoculated |10,529 | 1489 |1 in 7.07 | 329 | 1 in 32 |1 in 4.52 |

|Inoculated | 1,705 | 35 |1 in 48.7 | 8 | 1 in 213 |1 in 4.4 |

+-------------+-------+------+----------+-------+----------+----------+

The wide difference between the two groups, as regards the incidence

of the disease, is well marked; but the case-mortality is practically

the same in each group. (The statistics of the General Hospital,

Ladysmith, also tell in favour of the preventive treatment: see

Surgeon-Major Westcott's letter, _British Medical Journal_, 20th July

1901, in answer to Dr. Melville's letter, _British Medical Journal_,

20th April 1901.)

3. _The Portland Hospital: Modder River and Bloemfontein_. The

_British Medical Journal_, 10th November 1900, contains an account by

Dr. Tooth of the cases of typhoid in this hospital. Concerning the

preventive treatment, he says: "The experience of my colleague Dr.

Calverley and myself may be of interest, though we fear that the

numbers are too few for safe generalisation.

"_Personnel of the Portland Hospital._ We take first the relation of

disease and inoculation among the _personnel_ of the hospital.

Twenty-four non-commissioned officers, orderlies, and servants of the

Portland Hospital, and 4 of the medical staff, were inoculated on the

voyage out. All these showed the local symptoms at the time; that is,

pain, stiffness, and local erythema; 17 also presented well-marked

constitutional symptoms--general feeling of illness, fever, and

headache. Of the orderlies, 9 had enteric fever subsequently. Two had

refused inoculation, and both of these had the disease very severely;

in fact one died. Of the inoculated cases, 5 had the disease lightly,

and 2 fairly severely. One of the sisters had the disease rather

severely, and she had not been inoculated.

"_Officers and men admitted to the Portland Hospital._ We had under

treatment at the Portland Hospital 231 cases of enteric fever, most of

which came under our care at Bloemfontein. We have not included in

these figures a number of patients who came in convalescent for a

short time only, and on their way to the base, and who would therefore

appear in the admission and discharge book of the hospital. If we did

so, of course our percentages would be lower. Of these 231 patients,

53 had been inoculated at home or on the voyage out, and of them 3

died, making a percentage of deaths among the inoculated of 5.6 per

cent.; 178 had not been inoculated, of whom 25 died; that is, a

mortality among the non-inoculated of 14 per cent. The general

mortality in enteric fever with us was 28 deaths out of 231 cases;

that is, 12.1 per cent., which seems to compare favourably with the

experience of the London hospitals.

"It is interesting to record our experience among the officers taken

separately. Thirty-three officers were admitted with enteric fever; 21

had been inoculated; that is, 63.6 per cent.; a much larger percentage

than among the men. Only one of these officers died, and he had not

been inoculated.

"These figures are small, but such as they are they are significant,

and they dispose us to look with favour upon inoculation. So also does

our clinical experience with our patients, for among the inoculated

the disease seemed to run a milder course."

4. _No. 9 General Hospital, Bloemfontein._ The _Medical Chronicle_ for

January 1901 contains an account, by Dr. J. W. Smith, of the work of

this hospital. He says: "The general impression amongst the medical

officers in our hospital was that a single inoculation probably did

not confer an immunity lasting very long--the lapse of time differing

in individuals--and also that there was a tendency in the cases of

enteric in inoculated patients to abort at the end of ten or fourteen

days. I should say, however, that a very considerable number of our

detachment who had been inoculated suffered from enteric, of whom 4 at

least died. Of the medical staff, the only member of the junior staff

who had not been inoculated died of enteric."

5. _Scottish National Red Cross Hospital, Kroonstadt._ The _British

Medical Journal_, 12th January 1901, contains an account of the work

of this hospital by Surgeon-Colonel Cayley, Officer in Charge. He

says: "The first section of the hospital, consisting of 61

persons--officers, nursing sisters, and establishment--left

Southampton on 21st April 1900. During the voyage out, all except 4

were inoculated twice, at an interval of about ten days; 2 were

inoculated once; and 2 (who had had typhoid) were not inoculated.

Immediately we reached the Cape, the hospital was sent up to

Kroonstadt in the Orange River Colony, and remained there as a

stationary hospital till the middle of October. During this period

there were always many cases of enteric under treatment in hospital.

Further, some of the medical officers and student orderlies had charge

of the Kroonstadt Hotel temporary hospital, which was crowded up with

enteric cases; and the nursing sisters, for three weeks, did duty in

the military hospitals at Bloemfontein in May and June, when enteric

fever was at its worst. There was not a single case of enteric among

the _personnel_ of this first section of the hospital.

"The second section of the hospital--medical officers, nurses, and

establishment, 82 in all--left Southampton in May 1900. On board ship

nearly all of them were inoculated, but many of them only once. The

material for inoculation had been on board for some time, and was not

so fresh as in the first instance. Of this second section, 1 nurse had

enteric at Kroonstadt. She was the only one, out of a total of 36

nurses, who suffered from enteric; and she was the only nurse who was

not inoculated, excepting the 2 who were protected by a previous

attack of enteric. A third section of the hospital, consisting of 4

medical officers and 16 nurses, went out in July; they were all

inoculated, and none of them had enteric.

"Of the second section, 5 orderlies had enteric fever at Kroonstadt,

of whom 2 died. Of these 5, there were 2 inoculated (once) and 3

non-inoculated. Of the 2 who died, 1 had been once inoculated, the

other had not been inoculated."

6. _Meerut, India._ The _British Medical Journal_, 9th February 1901,

gives a short note by Professor Wright on inoculations in the 15th

Hussars. He says: "Through the kindness of Lieutenant-General Sir

George Luck, commanding the Bengal Army, I am permitted to publish the

following officially compiled statistics, dealing with the effects of

anti-typhoid inoculations in the case of the 15th Hussars:--

_From 22nd October 1899 to 22nd October 1900._

+---------------+---------+-----------+------+-------+

| | | | | |

+---------------+---------+-----------+------+-------+

|Officers | 22 | 19 | 0 | 0 |

|N.C.O. and Men | 481 | 317 | 2 | 1 |

|Women | 36 | 24 | 0 | 0 |

+---------------+---------+-----------+------+-------+

+---------------+-----------+------+-------+

| |Not | | |

+---------------+-----------+------+-------+

|Officers | 3 | 0 | 0 |

|N.C.O. and Men | 164 | 11 | 6 |

|Women | 12 | 0 | 0 |

+---------------+-----------+------+-------+

It would thus appear that the incidence of enteric in the inoculated

was represented by 0.55 per cent., and the mortality by 0.27 per

cent.; while the incidence in the uninoculated was 6.14 per cent., and

the death-rate 3.35 per cent."

If the inoculated had suffered equally with the uninoculated, they

would have had 22 cases with 11 deaths, instead of 2 cases with 1

death.

7. _The Edinburgh Hospital, South Africa._ The _Scottish Medical and

Surgical Journal_, March 1901, contains an account of the work of the

Edinburgh Hospital, by Dr. Francis Boyd. Of the staff, 58 were

inoculated (27 once, and 31 twice). Among these 58, there were 9

cases of typhoid fever, with I death, in a patient who had old mitral

disease. "Our experience has been that, while inoculation appears to

modify the disease, completely modified attacks are met with in the

uninoculated. Again, very severe attacks, with complications and

relapse, occur in those who have been inoculated. One cannot from this

conclude that inoculation has been valueless, for had not the patient

been inoculated, the attack might have been still more severe."

8. _Egypt and Cyprus._ The _British Medical Journal_, 4th May 1901,

gives a short note by Professor Wright on inoculations during 1901 in

Egypt and Cyprus. He says: "I am indebted to the kindness of Colonel

W. J. Fawcett, R.A.M.C., Principal Medical Officer in Egypt, for the

following statistics dealing with the incidence of enteric fever, and

the mortality from the disease, for the year 1900, in the inoculated

and uninoculated among the British troops in Egypt and Cyprus:--

+------------------------------------------------------------------+

|-------------+--------------+------+-------+----------+-----------|

|Uninoculated | 2669 | 68 | 10 | 2.50 | 0.40 |

|Inoculated | 720 | 1 | 1 | 0.14 | 0.14 |

+------------------------------------------------------------------+

These figures testify to a nineteen-fold reduction in the number of

attacks of enteric fever, and to a threefold reduction in the number

of deaths from that disease, among the inoculated.... The only case

which occurred among the inoculated was that of a patient admitted to

hospital on the thirty-third day after inoculation. It would seem that

the disease was in this case contracted before anything in the nature

of protection had been established by the inoculation."

9. _Imperial Yeomanry Hospital, Pretoria._ Dr. Rolleston, Consulting

Physician to this hospital, writes in the _British Medical Journal_,

5th October 1901: "Among the _personnel_ of the hospital (17 medical

officers, 50 nursing sisters, 83 orderlies, etc.), total, 150, there

were 22 cases of enteric fever, or an incidence of 14.6 per cent. Of

the 150, 35 were inoculated, and of these, 6, or 17 per cent.,

suffered from enteric; while, of 115 non-inoculated members of the

_personnel_, 16, or 13.9 per cent., suffered from enteric fever; the

percentage is therefore higher among the inoculated. There were 2

deaths, both in non-inoculated patients. In 100 cases of enteric fever

among non-commissioned officers and men, taken mainly from

convalescent patients, only 8 had been previously inoculated; there

were 3 fatal cases, all among non-inoculated patients. Among 42

officers who had enteric, no fewer than 19 had been previously

inoculated; 6 of these 19 cases were severe in character, but none

were fatal; of the 23 non-inoculated cases, 7 were severe, and of

these 7, 3 ended fatally. The interval between inoculation and the

subsequent incidence of enteric fever varied between one and

twenty-one months, but in only four instances was the interval less

than six months. The average interval between inoculation and the

onset of enteric fever in these 19 cases was thirty-eight weeks.

"As far as these scanty figures go, they point to the conclusion (1)

that anti-typhoid inoculation does not absolutely protect against a

future attack of typhoid fever; (2) that when enteric occurs in an

inoculated person, there is, as a rule, an interval of about six

months; (3) that inoculation protects against a fatal termination to

the disease."

10. _Richmond Asylum, Dublin._ The _British Medical_ _Journal_, 26th

October 1901, contains a note by Professor Wright on an outbreak of

typhoid in this asylum during August to December 1900. Inoculations

were begun on 6th September, by Dr. Cullinan, and by 30th November 511

persons were inoculated. After careful criticism of all doubtful

cases, Professor Wright gives the following figures:--

_Comparative Incidence of Typhoid Fever in Inoculated and

Non-Inoculated, calculated upon the average strength of the

representative groups during the period intervening between the

commencement of the inoculations and the termination of the

epidemic._

+--------------+---------+-------+-------+----------+----------+

+--------------+---------+-------+-------+----------+----------+

|Uninoculated | 298 |30(-1?)| 4 | 10.1 | 1.3 |

|Inoculated | 339 | 5(+1?)| 1 | 1.3 | 0.3 |

+--------------+---------+-------+-------+----------+----------+

"It may be noted," he says, "that the result is in conformity with

that of all the statistical returns of anti-typhoid inoculation which

have reached me."

11. _Deelfontein._ The _Lancet_, 18th January 1902, contains a paper

by Dr. Washbourn and Dr. Andrew Elliot, on 262 cases of typhoid fever

in the Imperial Yeomanry Hospital at Deelfontein during the year March

1900 to March 1901. (See Dr. Washbourn's earlier letter, _Brit. Med.

Jour._, 16th June 1900.) They say: "In 211 of our cases, it was

definitely recorded whether the patient had been inoculated or not:

186 of these cases had not been inoculated, with 20 deaths, or a

mortality of 10.7 per cent.; 25 had been inoculated, with 4 deaths, or

a mortality of 16 per cent. The mortality was thus higher among the

inoculated than among the non-inoculated." Of the _personnel_ of the

hospital, there were 59 inoculated, with 4 cases, and 25 not

inoculated, with 4 cases.

12. _Winburg._ The _Lancet_, 5th April 1902, contains a short note by

Professor Wright, on the 5th Battalion, Manchester Regiment. He says:

"In view of the dearth of statistics bearing on the incidence of

typhoid fever in South Africa in inoculated and uninoculated persons

respectively, the following, for which I am indebted to Lieutenant J.

W. West, R.A.M.C., Winburg, Orange River Colony, may not be entirely

without interest. The statistics here in question give the results

obtained in the case of the 5th Battalion, Manchester Regiment, for

the six months which have elapsed since their landing in South Africa.

The figures, which relate to a total strength of 747 men and officers

under observation, are as follows:--

+--------------+---------+-------+-------+----------+----------+

+--------------+---------+-------+-------+----------+----------+

|Uninoculated | 547 | 23 | 7 | 4.2 | 1 in 3.3 |

|Inoculated | 200 | 3 | 0 | 1.5 | 0 |

+--------------+---------+-------+-------+----------+----------+

"The three attacks in the inoculated are reported to have been of

exceptionally mild type, contrasting in a striking manner with the

severe attacks which occurred in the uninoculated. At the time of

sending in the report, some of the uninoculated patients were 'not yet

out of danger.'"

* * * * *

Certainly, these instances show a good balance of lives saved, not

only under the adverse conditions of the war, but also in Egypt,

India, and the United Kingdom. But the bacteriological work on typhoid

fever has been directed also to the working out of a very different

problem: and that is the method of diagnosis which is called "Widal's

reaction." The practical uses of this reaction are of the utmost

importance. It is the outcome of work in different parts of the

world--by Wright and Semple and Durham in England, Chantemesse and

Widal in France, Pfeiffer and Kolle and Grüber in Germany, and many

more. The first systematic study of it was made by Durham and

Pfeiffer; and Widal's name is especially associated with the

application of their work to the uses of practice. Admirable accounts

of the whole subject are given by Dr. Cabot in his book, _The

Serum-Diagnosis of Disease_ (Longmans, 1899), and by Mr. Foulerton in

the _Middlesex Hospital Journal_, October 1899 and July 1901.

Widal's reaction is surely one of the fairy tales of science. The

bacteriologist works not with anything so gross as a drop of blood,

but with a drop of blood fifty or more times diluted; one drop of this

dilution is enough for his purpose. Take, for instance, an obscure

case suspected to be typhoid fever: a drop of blood taken from the

finger is diluted fifty or more times, that the perfect delicacy of

the test may be ensured; a drop of this dilution is mixed with a drop

of nutrient fluid containing living typhoid bacilli, and a drop of

this mixture of blood and bacilli is watched under the microscope:--

"The motility of the bacilli is instantaneously or very quickly

arrested, and in a few minutes the bacilli begin to aggregate

together into clumps, and by the end of the half-hour there will

be very few isolated bacilli visible. In less marked cases, the

motility of the bacilli does not cease for some minutes; while

in the least marked ones the motility of the bacilli may never

be completely arrested, but they are always more or less

sluggish, while clumping ought to be quite distinct by the end

of the half-hour."

The result of this clumping is also plainly visible to the naked eye,

by the subsidence of the agglutinated bacteria to the bottom of the

containing vessel: and thus an easy practical mode of diagnosis is

afforded by it.

As with typhoid, so with Malta fever, cholera, and some other

infective diseases. And the unimaginable fineness of this reaction

goes far beyond the time of the disease. Months, even years, after

recovery from typhoid, a fiftieth part of a drop of the blood will

still give Widal's reaction: and it has been obtained in an infant

whose mother had typhoid before it was born. A drop of dried blood,

from a case suspected to be typhoid, may be sent a hundred miles by

post to be tested; and typhoid, like diphtheria, may now be submitted

to the judgment of an expert far away, and the answer telegraphed

back. It would be difficult to exaggerate the practical importance of

this reaction for the early diagnosis of cases of typhoid fever,

especially those cases that appear, at the onset, not severe.

MALTA FEVER

The specific organism of Malta fever (Mediterranean fever), the

_bacillus Melitensis_, was discovered in 1887 by Surgeon-Major David

Bruce, of the Army Medical Staff. Its nature and action were proved by

the inoculation of monkeys. The use of Widal's reaction is of great

value in this disease:--

"The diagnosis of Malta fever from typhoid is, of course, a

highly important practical matter. It is exceedingly difficult

in the early stages." (Manson, _loc. cit._)

As with typhoid, so with Malta fever, Netley led the way to the

discovery of an immunising serum. In the course of the work, one of

the discoverers was by accident infected with the disease:--

"He was indisposed when he went to Maidstone to undertake

anti-typhoid vaccination, and after fighting against his illness

for some days, he was obliged to return to Netley on 9th

October. Examination of blood-serum (Widal's reaction) showed

that he was suffering from Malta fever. It appears that he had

scratched his hand with a hypodermic needle on 17th September,

when immunising a horse for the preparation of serum-protective

against Malta fever; and his blood, when examined, had a typical

reaction on the micrococcus of Malta fever in 1000-fold

dilution. The horse, which has been immunised for Malta fever

for the last eight months, was immediately bled, and we are

informed that the patient has now had two injections, each of 30

cub. cm. of the serum. He is doing well, and it is hoped that

the attack has been cut short." (_British Medical Journal_, 16th

October 1897.)

About fifty cases had up to September 1899 been treated at Netley

"with marked benefit: whereas they found that all drug-treatment

failed, the antitoxin treatment had been generally successful."[36] A

good instance of the value of the serum-treatment of Malta fever is

published in the _Lancet_, 15th April 1899. For a later account of

this treatment and of its efficacy, see the _Philadelphia Medical

Journal_, 24th November 1900.

[36] For the whole subject, see _Lancet_, 9th September 1899,

paper by Surgeon-Major Birt and Surgeon-Captain Lamb. Two other

cases of accidental inoculation occurred at Netley.

Another point is noted by Sir Patrick Manson, in his recent Lane

Lectures (Constable, 1905). "For some time back," he says, "a

commission of experts, working under the direction of the Royal

Society, has been studying this disease in Malta. The commission has

accumulated much detailed information; but the most important

observation it has published is the fact that a large percentage of

the goats in Malta are infected with _Micrococcus melitensis_, and

that the milk of the infected goats contains the bacterium. May not

this account for the great prevalence of Mediterranean fever there and

in other places having perhaps a similar milk-supply?"

THE MOSQUITO: MALARIA, YELLOW FEVER, FILARIASIS

Within the last few years, it has been proved that the mosquito is an

intermediate host, between man and man, of malaria, yellow fever, and

filariasis (elephantiasis).[37] Just as the grosser parasites, the

tapeworms, must alternate between man and certain animals, and cannot

otherwise go through their own life-changes and reproduce their kind,

so the micro-parasites that are the cause of malaria alternate between

man and the mosquito, having the mosquito as an intermediate host.

These organisms, once they get into the mosquito, pick out certain

structures, and there carry out a definite cyclical phase of their

lives, whereby their progeny make their way into the stylets of the

mosquito, and so get back to man, who is their "definite host." Thus,

malaria is not, strictly speaking, a disease of man; it is one phase

in man of micro-organisms that have another phase in mosquitoes. So

also with filariasis; the filariæ in man, their ova, and their

embryo-worms, are one phase of filariasis; and the embryo-worms in

certain structures of the mosquito are another phase. The _plasmodium

malariæ_ and the _filaria_ are instances of a law of animal life that

holds good also of plant life:--

"All plants and animals possess parasites, and thousands of

different species of parasites have been closely studied by

science; we therefore know much about their general ways of

life. As a rule, a particular species of parasite can live only

in the particular species of animal in which, by the evolution

of ages, it has acquired the power of living. It is therefore

not enough for the parasites of an individual animal--say a

man--to be able to multiply within that individual, but they

must also make arrangements, so to speak, for their progeny to

enter into and infect other individuals of the same species.

They cannot live for ever in one individual; they must spread in

some way or other to other individuals.

"The shifts made by parasites to meet this requirement of their

nature are many and various, and constitute one of the wonders

of nature. Some scatter their spores and eggs broadcast in the

soil, water, or air, as it were in the hope that some of them

will alight by accident on a plant or animal suitable for their

future growth. Many parasites employ, in various ways, a second

species of animal as a go-between. Thus, some tapeworms, and the

worms which cause trichinosis, spend a part of their lives in

the flesh of swine, and transfer themselves to human beings when

the latter eat this flesh. To complete the cycle, the parasites

return to swine from human offal; so that they propagate

alternately from men to swine, and from swine to men. The

blood-parasites which cause the deadly tsetse-fly disease among

cattle in South Africa are transferred from one ox to another on

the proboscis of the ox-biting or tsetse-fly. The progeny of the

flukes of sheep enter a kind of snail, which spreads the

parasites upon grass. The progeny of the guinea-worm of man

enter a water-flea. The progeny of the parasites which cause

Texas cattle-fever, and which are very like the malarial

parasites, live in cattle-ticks, and are transferred by the

young of these ticks into healthy cattle." (Ross, _Malarial

Fever_, 1902.)

[37] For Dr. Graham's experiments at Beyrout, which seem to prove

that the mosquito can also convey dengue or dandy-fever, see the

_New York Medical Record_, 8th February 1902.

1. MALARIA

The _plasmodium malariæ_ was discovered by Laveran in 1880, in the

blood of malarial patients. For many years his work stopped there,

because it was impossible to find the _plasmodium_ in animals: "the

difficulties surrounding the subject were so great that this discovery

seemed to be almost hopeless." In 1894, Sir Patrick Manson--who had

proved mosquitoes to be the intermediate host in the case of the

parasitic nematode _filaria_--suggested, as a working theory of

malaria, that the plasmodium was carried by mosquitoes. This belief,

not itself new, he made current coin. He observed that there is a

flagellate form of the plasmodium, which only comes into existence

after the blood has left the body: and he suggested that the flagella

might develop in the mosquito as an intermediate host, a halfway-house

between man and man. Then, in 1895, Ross set to work in India, keeping

and feeding vast numbers of mosquitoes on malarial blood; and for two

years without any conclusive result. About this time came MacCallum's

observations, at the Johns Hopkins University, on a parasitic

organism, _halteridium_, closely allied to the plasmodium malariæ; he

showed that the flagella of the halteridium are organs of

impregnation, having observed that the non-flagellated form, which he

regarded as the female, after receiving one of the flagella, changed

shape, and became motile. In August 1897, Ross found bodies,

containing pigment like that of the malarial parasite, in the outer

coat of the stomach of one kind of mosquito, the grey or

dapple-winged mosquito, _Anopheles maculipennis_, that had been fed

on malarial blood. In February 1898, he was put on special duty under

the Sanitary Commissioner with the Government of India, to study

malaria, and started work again in Calcutta:--

"Arriving there at a non-fever season, he took up the study of

what may be called 'bird malaria.' In birds, two parasites have

become well known--(1) the halteridium, (2) the proteosoma of

Labbé. Both have flagellated forms, and both are closely allied

to the plasmodium malariæ. Using grey mosquitoes and

proteosoma-infected birds, Ross showed by a large number of

observations that it was only from blood containing the

proteosoma that pigmented cells in the grey mosquito could be

got; therefore that this cell is derived from the proteosoma,

and is an evolutionary stage of that parasite. Next, Ross

proceeded to find out its exact location, and found that it lay

among the muscular fibres of the wall of the mosquito's stomach.

It grows large (40-70 micro-millimetres) and protrudes from the

external surface of the stomach, which under the microscope

appears as if covered with minute warts." (Manson, at Edinburgh

meeting of British Medical Association, 1898.)

These pigmented spherical cells give issue to innumerable swarms of

spindle-shaped bodies, "germinal rods"; and in infected mosquitoes

Ross found these rods, in the glands that communicate with the

proboscis. Thus the evidence was complete, that the plasmodium

malariæ, like many other parasites, has a special intermediate host

for its intermediate stage of development; and that this host is the

dapple-winged mosquito. It is impossible to over-estimate the infinite

delicacy and difficulty of Ross's work; for instance, in his "Abstract

of Recent Experiments with Grey Mosquitoes," he says that "out of 245

grey mosquitoes fed on birds with proteosoma, 178, or 72 per cent.,

contained pigmented cells; out of 249 fed on blood containing

halteridium, immature proteosoma, &c., not one contained a single

pigmented cell." Another time (April 1898) he counted these

pigment-cells under the microscope:--

"Ten mosquitoes fed on the sparrow with numerous proteosoma

contained 1009 pigmented cells, or an average of 101 each. Ten

mosquitoes fed on the sparrow with moderate proteosoma contained

292 pigmented cells, or an average of 29 each. The mosquitoes

fed on the sparrow with no proteosoma contained no pigmented

cells."

Finally, he completed the circle of development by infecting healthy

sparrows by causing mosquitoes to bite them.

In 1899, there went out a German Commission to German East Africa, a

Royal Society's Commission to British Central Africa, and an

expedition from the Liverpool School of Tropical Medicine; in 1900,

another German Commission, this time to the East Indies, and another

expedition from the Liverpool School; by July 1901, the Liverpool

School was organising its seventh expedition. Italy, of course, has

given infinite study to the disease:--

"It has been decided that, in addition to the stations of

observation and experiment in the provinces of Rome, Milan,

Cremona, Mantua, Gercara, Foggia, Lecce, others shall be

established in the provinces of Udine, Verona, Vicenza, Padua,

Ravenna, Pisa, Basilicata, and Syracuse. Besides epidemiological

researches, applications on a large scale will be made of

preventive measures for the protection of the agricultural

population against the scourge. Another extensive experiment on

the prophylaxis of malaria will be made on the Emilian

littoral. Moreover, in all the malarious regions of the Italian

peninsula the provincial and communal administrations and many

private persons will co-operate in the application of preventive

measures. From all this it may be gathered that during the

summer and autumn the war against malaria will be carried on in

Italy with great vigour and thoroughness." (_British Medical

Journal_, 6th July 1901.)

In India, the work started in 1900 by the Royal Society Commissioners,

and by the Nagpur Conference, has been widely extended; especially by

such researches as those of Major Buchanan, I.M.S., Superintendent of

the Central Jail, Nagpur. The following paragraph, from the report of

the Sanitary Commissioner with the Government of India, refers to

Major Buchanan's published work, _Malarial Fevers and Malarial

Parasites in India_:--

"A remarkable note is struck at the outset, in the

acknowledgment made, by the author, of the capable assistance

rendered in these researches by several of his Burmese

prisoners, whom he trained to the use of the microscope, and who

soon became expert in detecting and distinguishing the various

kinds of parasites.... Besides a systematic clinical account of

the different forms of fever and the associated parasites, which

is the first attempt of the kind in India, there are a summary

of the facts showing the relation of the seasonal prevalence of

_Anopheles_ to the incidence of attacks; experiments exhibiting

the protective effects of mosquito-curtains;

inoculation-experiments; researches on the blood-parasites of

birds; and many other points.... Nor can we pause to notice the

many attempts now being made by health officers and others to

pursue the methods of prophylaxis indicated; these efforts are

necessarily in the tentative stage, but, so far, and especially

where carried out in connection with small communities and

institutions, they are giving promise of gratifying success."

The famous experiment made by Dr. Sambon and Dr. Low in 1900, must be

recalled here:--

"Dr. Luigi Sambon and Dr. G. C. Low, both connected with the

London School of Tropical Medicine, volunteered to live from

June till October, that is to say, through what may be called

the height of the malaria season, in a part of the Campagna near

Ostia, which is so infested by the disease that no one who

spends a night there under ordinary conditions escapes the

effect of the poison. Dr. Sambon, Dr. Low, Signor Terzi, and

their servants, have now exposed themselves to the pestilential

influence of this valley of the shadow of death for over two

months. They live in a mosquito-proof hut; they take no

quinine or other drug which might be regarded as prophylactic.

Not one of the experimenting party has the least sign of

infection.[38]...

"What for practical purposes may be regarded as an experiment of

the same kind is being conducted in West Africa. Dr. Elliot, a

member of the Liverpool expedition sent to Nigeria some time ago

to investigate the subject of malarial fever, has recently

returned to this country. He reports that the members of the

expedition have been perfectly well, although they have spent

four months in some of the most malarious spots. They lived

practically amongst marshes and other places hitherto supposed

to be the most deadly. They have not kept the fever off by the

use of quinine, and they attribute their immunity to the careful

use of mosquito-nets at night." (_British Medical Journal_, 22nd

September 1900.)

[38] Sir Patrick Manson, in the _British Medical Journal_, 29th

September 1900, gives the following account of this

experiment:--"A wooden hut, constructed in England, was shipped to

Italy and erected in the Roman Campagna, at a spot ascertained by

Dr. L. Sambon, after careful inquiry, to be intensely malarial,

where the permanent inhabitants all suffer from malarial cachexia,

and where the field-labourers, who come from healthy parts of

Italy to reap the harvest, after a short time all contract fever.

This fever-haunted spot is in the King of Italy's hunting-ground

near Ostia, at the mouth of the Tiber. It is waterlogged and

jungly, and teems with insect life. The only protection employed

against mosquito-bite and fever by the experimenters who occupied

this hut was mosquito-netting, wire screens in doors and windows,

and, by way of extra precaution, mosquito-nets round their beds.

Not a grain of quinine was taken. They go about the country quite

freely--always, of course, with an eye on _Anopheles_--during the

day, but are careful to be indoors from sunset to sunrise. Up to

21st September, the date of Dr. Sambon's last letter to me, the

experimenters and their servants had enjoyed perfect health, in

marked contrast to their neighbours, who were all of them either

ill with fever, or had suffered malarial attacks."

A similar "experiment," of the utmost importance, was made in 1900 by

Professor Grassi. It concerned the workmen and their families along

the Battipaglia-Reggio railway, 104 in all, including 33 children. The

great majority of them had suffered from malaria in the preceding

year; and only 11, including 4 children, had never suffered from it.

Pending the arrival of the malarial season, quinine was given to all

who needed it. The first _Anopheles_ with its salivary glands infected

was found on 14th June. Twelve days later came a case of malaria

outside the "zone of experiment," in a person who had never had

malaria before. The twelve days correspond to the incubation-period

after infection. _Anopheles_ having come, and the malarial season with

him, the experiment was begun. The houses were carefully protected

with wire netting, chimneys and all; the _siesta_ was taken under wire

netting; the workmen, if they were out in the evening or at night,

wore veils and gloves; and _Anopheles_ was to be killed wherever he

was found. Quinine was altogether given up and forbidden, except for

three workmen who had escaped or evaded its use before June, and had,

indeed, never before been treated with quinine; one of them, moreover,

had been sleeping outside the zone of experiment in July. Except these

three, all the 104 and their doctors remained absolutely free from

malaria up to 16th September, the date of Professor Grassi's report:--

"Rightly to estimate the value of these facts, it is necessary

briefly to describe the surroundings of the protected area.

Towards the north, coming from Battipaglia, three railway

cottages are situated, at a distance of 1, 2, and 3 kilometres

respectively. The 25 inhabitants of these cottages, although

they were put under the tonic and quinine treatment in the

non-malarial season, all without exception were taken ill with

malarial fevers, in many cases obstinate."

Experiments of voluntary exposure to bite from an infected mosquito

were made at or about this time, in London, New York, Italy, and

India. The London "consignment" of mosquitoes had been allowed to bite

a malaria-patient in Rome. The experiment had to be very carefully

planned:--

"To have sent mosquitoes infected with malignant tertian

parasites might have endangered the life of the subject of the

experiment; and quartan-infected insects might have conferred a

type of disease which, though not endangering life, is extremely

difficult to eradicate. The cases, therefore, on which the

experimental insects were fed had to be examples of pure benign

tertian--a type of case not readily met with in Rome during the

height of the malarial season; the absolute purity of the

infection could be ascertained only by repeated and careful

microscopic examination of the blood of the patient." (_British

Medical Journal_, 29th September 1900.)

The mosquitoes were forwarded, through the British Embassy in Rome, to

the London School of Tropical Medicine. The two brave gentlemen who

let themselves be bitten by some thirty of the mosquitoes were in due

time attacked by malaria, and the tertian forms of the parasite were

found in their blood. Nine months later, one of them had a relapse,

and the parasite was again found in his blood.

It is not possible to sum up the wealth of work on malaria published

in 1900-1901. Good accounts of it are in the Transactions of the

Section of Tropical Diseases, at the Annual Meeting of the British

Medical Association (Cheltenham, 1901), and in the Thompson Yates

Laboratories Reports, vol. iii., pt. 2, 1901. Everything had to be

studied: not only the nature and action of the _plasmodium_ in all its

phases, but also the whole natural history and habits of the

_Anopheles_ of different countries; and, above all, the incidence of

the disease on natives and on Europeans in China, India, and Africa.

All that can be done here is to try to indicate the principal lines

followed in the present world-wide campaign against malaria. The

following paragraphs are taken mostly from the accounts given by Dr.

Christophers and Dr. Annett, in the Thompson Yates Laboratories

Report, 1901:--

1. _Elimination of the Infection at its Source._ This is the method

employed with success by Professor Koch in New Guinea, viz., to search

out all cases of malaria (the concealed ones in particular), and to

render them harmless by curing them with quinine. At Stephansort, by

thus hunting up all infected cases, and as it were, sterilising them

by the systematic administration of quinine, he was able to achieve a

great reduction of the disease in the next malarial season, even

under adverse conditions. He says, in his report to the German

Government: "The results of our experiment, which has lasted nearly

six months, have been so uniform and unequivocal that they cannot be

regarded as accidental. We may assume that it is directly owing to the

measures we have adopted that malaria here has, in a comparatively

short time, almost disappeared."

This method, of course, is applicable only in small communities; and,

within these limits, it may become one of the most valuable of all

methods, being, like the quality of mercy, a blessing both to him who

gives and to him who taketh. But it cannot be practised on a vast

scale. This difficulty is well put by Sir William MacGregor, K.C.M.G.,

Governor of Lagos, West Africa:--

"In all probability, the day will come before long, when

newly-appointed officers for places like Lagos will have to

undergo a test as to whether they can tolerate quinine or not. A

man that cannot, or a man that will not, take quinine, should

not be sent to or remain in a malarial country, as he will be

doing so at the risk of his own life, _and to the danger of

others_.... The great difficulty is how to extend this treatment

beyond the service, more particularly to the uneducated masses

of the natives. It is simply impossible to protect the whole

population by quinine administered as a prophylactic. In the

first place, the great mass of natives would not take the

medicine; and, in the second place, the Government could not

afford to pay for the 70 tons of quinine a year that would be

required to give even a daily grain dose to each of 3,000,000 of

people."

2. _Segregation of Europeans from Natives._ This method is strongly

advocated by the members of the Nigeria Expedition of the Liverpool

School (1900). The distance of removal to half a mile is considered

sufficient: "Considerable evidence has now been accumulated to prove

that the distance which is traversed by a mosquito is never very

great, and extremely rarely reaches so much as half a mile." The

arguments in favour of this method of "segregation" are of so great

interest that they must be put here at some length. The drawback is

that the method cannot be followed everywhere to its logical issue

without some risk of giving offence, of seeming to abandon the native,

of damaging commerce, and so forth. But, short of this, much might be

done for the protection of Europeans in Africa:--

"This method is a corollary of the discovery that native

children in Africa practically all contain the malaria parasite,

and are the source from which Europeans derive malaria. Koch

showed in New Guinea that in most places infection was very

prevalent in native children, so much so that in some villages

100 per cent. of those examined contained parasites. He also

showed that, as the children increased in age, immunity was

produced, so that in the case of adults a marked immunity was

present, and malarial infection was absent. The Malaria

Commission showed, independently, that a condition of universal

infection existed among the children of tropical Africa,

associated with an immunity of the adults. This infection in

children had many remarkable characteristics. The children were

in apparent health, but often contained large numbers of

parasites, and a small proportion only of the children failed to

show some degree of infection.... The Liverpool School

Expedition found a similar condition of affairs in all parts of

Nigeria visited by them.

"With a knowledge of the ubiquity of native malaria, the method

of infection of Europeans becomes abundantly clear. The reputed

unhealthiness or healthiness of stations is seen at once to be

dependent on the proximity or non-proximity of native huts. The

attack of malaria after a tour up-country, the malaria at

military stations like Prah-su, the abundance of malaria on

railways, are all explicable when the extraordinary condition of

universal native infection is appreciated. It is evident that,

could Europeans avoid the close proximity of native huts, they

would do away with a very obvious and great source of

infection.... When it is understood that each of these huts

certainly contains many children with parasites in their blood,

and also scores or hundreds of _Anopheles_ to carry the

infection, then the frequency with which Europeans suffer from

malaria is scarcely to be wondered at.... The accompanying plan

is that of a new railway settlement on the Sierra Leone Railway.

Miles of land free from huts exist along the line, but the close

neighbourhood of native huts has been selected. At the time of

building of these quarters, it lay in the power of the engineers

to have a malaria-free settlement; instead of which, by the

non-observance of a simple fact, the station is most malarious:

in this particular instance, much ingenuity has been shown in

providing each set of European quarters with plenty of malarial

infection. In towns only is there any difficulty in carrying out

the principle of segregation. In two instances, however, this

has been carried out in towns, with the result that the

segregated communities of Europeans are notoriously the most

healthy on the West Coast. Even when no scheme of complete

segregation can be carried out, the principle should always be

borne in mind, and, whenever opportunity offers, huts should be

removed, and European houses built in the open.... It is almost

universally the rule in West Africa to find European houses

built round by native quarters, a practice which long experience

in India has taught Europeans to avoid carefully. At Old

Calabar, many of the factories are almost surrounded, except in

front, by native habitations; similarly, at Egwanga, the small

native town is built by the side and back of one of the

factories. Also at the Niger Company's factory at Lokoja, the

native houses are very close up to the Company's boundary

railings. Akassa engineers' quarters may be, again, mentioned as

an example where the engineering artisans, chiefly natives of

Lagos, Accra, and Sierra Leone, are housed with their families

alongside the European house. A large proportion of these native

children were found by us to contain malarial parasites.

Similarly also at Asaba, the proximity of the barracks of the

Hausa soldiers, who have their wives and children with them, is

a dangerous menace to the officers at the Force House.

"Examples of the opposite condition of affairs might also be

given. For instance, at Old Calabar, the Government offices and

Consulate, Vice-Consulate, and medical house, are comparatively

free from malarial fever; it having been established that the

natives shall not build on the European side of the creek

separating the two slopes on which the native town and European

quarters are built. This creek is at a distance of about half a

mile from the houses mentioned."

It is plain, from these and other instances given by the members of

the Nigeria Expedition, that a modified sort of "segregation" can be

effected in many places, without any injury either to native feelings,

or to politics, or to commerce; and that by such segregation the risk

of malaria among Europeans in Africa would be diminished.

3. _Protection against Anopheles._ Manson, in his _Tropical Diseases_

(1905), says, "The question is often asked, Is there any other way by

which malaria can be contracted than through a mosquito-bite? For many

reasons, I believe not. It is difficult to prove a negative; but, so

far, there is no observation capable of bearing investigation that

would lead us to suppose that malaria can be acquired, under natural

conditions, except by mosquito-bite," All authorities are agreed

that, practically, the fight against malaria and the fight against

_Anopheles_ are one and the same thing; and the experiments by Sambon,

Low, and Grassi, show what can be done, in this war against the

mosquito, by way of defence. But what is practicable in Italy might

not be generally practicable on the West African coast; as Sir William

MacGregor says of Lagos:--

"It is not likely that in a place like Lagos as good results can

be obtained from the use of mosquito-proof netting as in Italy.

One great objection to it here is the serious and highly

disagreeable way it checks ventilation. This is a difficulty

that cannot be fully brought home to one in a cold climate. But,

in a low-lying, hot, and moist locality like Lagos, it comes to

be a choice of evils, to sit inside the netting stewed and

suffocated, or to be worried and poisoned by mosquitoes outside.

The netting is hardly a feasible remedy as regards native

houses. It is not possible to protect even European quarters

completely by it. Few officers or others are so occupied that

they could spend the day in a mosquito-proof room. Certain it is

that any man that suffers from the singular delusion that

mosquitoes bite only during the night, would have a speedy cure

by spending a few days, or even a few hours, in Lagos.

Operations here (September 1901) are being limited to supplying

one mosquito-proof room to the quarters of each officer. In this

he will be able to spend the evening free from mosquitoes if he

chooses to do so. The European wards of the hospital are

similarly protected."

The European in Africa, as Ross says, is generally neglectful of his

health; and the "unhealthiness" of the African coast is to some extent

due to the life that men lead there:--

"Let us compare the habits of a European in a business-house in

Calcutta with the habits of a European in West Africa. In

Calcutta he sleeps under a punkah or mosquito-net, or both; he

dresses and breakfasts under a punkah; in the evening he takes

vigorous exercise, and he dines under a punkah. He wears the

lightest possible clothing, he lives in a solid, cool, airy

house, and he obtains very good food; once in five or six years,

he returns to Europe for leave.... In Africa, the houses are

frequently very bad; in Freetown, for instance, they are the

same as the houses of natives, and are mingled with them. The

Anglo-African seems to imagine that he can live in the tropics

in the same manner as he lives in England. He seldom uses a

punkah, except perhaps for an hour at dinner-time, and, not

seldom, he neglects even the mosquito-net. The food is often, or

generally, execrable. Owing to the frequent absence of gymkhanas

and clubs, the exile obtains little suitable exercise."

But whatever risks the old resident may choose to take, the newcomer

can at least use a proper and efficient mosquito-net at night, and

avoid sleeping in a native house, and protect himself in these and the

like ways against malaria.

4. _The keeping down of Anopheles._ The breeding places of _Anopheles_

are ponds, swamps, and puddles, roadside ditches, tanks, and cisterns,

old disused canoes, and the like collections of stagnant water: also

the smaller receptacles that are more generally occupied by _Culex_,

such as broken bottles, old tins, pots, and calabashes, and barrels,

whatever will hold water--all the débris and broken rubbish round huts

or houses. In all these places, _Anopheles'_ eggs or larvæ are found;

and, with practice, it is easy to detect them. Of course, it is not

easy to wage war against the adult mosquito: the work is, _Venienti

occurrere morbo_, to organise gangs of workmen, or of prison labour,

and "mosquito brigades"; to clear the ground of cartloads of old

biscuit-tins, broken gin-bottles, and other dust-heap things, in and

around the place; to cover-in the cisterns, rain-barrels, and wells;

to clean pools and duck-ponds of weed, and stock them with minnows; to

put a film of kerosene to the puddles, or sweep them out, or fill them

up and turf them over; everywhere, to drain, and level, and clean-up

the surface soil; and everywhere, by these and the like methods, to

break the cycle of the life of the _plasmodium malariæ_:--

"Draining and cultivation where the land will repay the

expenditure, permanent and complete flooding where it will not,

and such flooding is possible; proper paving of unhealthy towns,

and the filling-in of stagnant, swampy pools; these--in other

words, all measures calculated to keep down mosquitoes--are the

more important things to be striven for in attempting the

sanitation of malarious districts. In England, in Holland, in

France, in Algeria, in America, and in many other places,

enormous tracts of country, which formerly were useless and

pestilential, have been rendered healthy and productive by such

means." (Manson.)

And, short of such great enterprises as Government works of drainage,

much has already been done, in many African towns, and in India, by

the work of a few men and women: not only by practical sanitary

improvements, but by insistent teaching and lecturing. For the

admirable results recently obtained in Ismailia, Algeria, Formosa, and

the Malay States, see the _Medical Annual_, 1905 and 1906.[39]

[39] This paper, by Dr. Stephens, gives also the reasons why

equally good results were not obtained at Mian Mir, Punjab. The

whole paper is of great interest.

Before leaving the subject of malaria, it must be added that the

discovery and study of the parasite which causes it have cleared up

the mystery of the specific action of quinine upon the disease. It

operates simply by its germicidal effect upon the microbe. But, beyond

this, we have now a clue which we never had before to guide us to the

most advantageous manner of administering the drug.

2. YELLOW FEVER

The specific organism of malaria may become active again and again in

the blood, causing relapses twenty years or more after the original

infection. The specific organism of yellow fever expends itself at

once, in one acute attack; and, if the patient recovers, he is

thenceforth more or less immune against infection. That the

inoculation of the disease, by the application of a single mosquito

recently contaminated, is calculated to produce a mild or abortive

attack less dangerous than the average attack among the

non-acclimatised, was known to Finlay, and was confirmed in 1899 by

the Army Commission of the United States.

Of the mortality of the disease, Sir Patrick Manson, in 1900, wrote as

follows:--

"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.

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.)

Good accounts of Fraser's and Calmette's work are given by Dr. Stone

in the _Boston Medical and Surgical Journal_, 7th April 1898, and by

Staff-Surgeon Andrews, R.N., in the _British Medical Journal_, 9th

September 1899. For other cases see the _Pioneer_, 10th August 1899,

the _Lancet_, 25th November 1899, and the _British Medical Journal_,

23rd December 1899. In one of these cases, recorded by Dr. Rennie, the

patient was, literally, at the point of death, but recovered after the

serum had been injected. Two cases have also been recorded of

cobra-bite during work in the laboratory: both of them recovered after

injection. "Every Government or private dispensary," says Surgeon

Beveridge, "should be supplied with antivenene, which is certainly the

best remedy for snake-bite available." The cases are few at present;

but it does not appear that the treatment has failed in any case; and,

with a new remedy of this kind, it is fairly certain that failures

would be published.

* * * * *

From all these instances in physiology, pathology, bacteriology, and

therapeutics, we come to consider the Act relating to experiments on

animals in the United Kingdom. Many subjects have been left out; among

them, the work of the last few years on the suprarenal glands and

adrenalin, and Dr. William Hunter's admirable work on pernicious

anæmia. No attempt has been made to describe the researches of experts

in many countries into the nature of malignant disease, or to guess

what may come of the discovery that mice can be immunised against that

form of cancer which occurs in mice and is inoculable from mouse to

mouse. Nothing has been said of the discovery that the African

sleeping-sickness is due to a blood-parasite carried by flies from man

to man. Nothing has been said about those discoveries in bacteriology

that have not yet been applied to practice, or of the many inventions

of medical and surgical practice that owe only an indirect debt to

experiments on animals. Artificial respiration, the transfusion of

saline fluid, the hypodermic administration of drugs, the use of

oxygen for inhalation, the torsion of arteries, the grafting of skin,

the transplantation of bone, the absorbable ligature, the diagnostic

and therapeutic uses of electricity, the rational employment of

blood-letting--all these good methods have been left out of the list;

only some facts have been presented, those that mark most clearly the

advance of knowledge and of practice, and stand up even above the rest

of the work. There they will stand, when we are all dead and gone: and

by them, as by landmarks, all further advance will be guided.

"The annual admissions _per mille_ for enteric fever amongst