Every now and then at an auspicious moment the world at large becomes aware that an important scientific discovery has been made. To the man in the street and even to such scientifically-trained persons as the physician or the engineer, the discovery comes from a clear sky.
They are not aware of the long series of steps, the slow, gradual advance which alone has made possible the culminating discovery which proves of great benefit to mankind. It is because of this lack of appreciation of the slow steps which are necessary that the ordinary scientific worker who makes no great discovery but is simply adding his small mite to the accumulated wealth of the nations is regarded by many as a useless dreamer and as a typically unpractical man.
During the last few years the attention of Canadians has been drawn to some of the results of scientific work carried out in Canadian universities, which have been recognized throughout the world. The wide recognition of these discoveries has cheered and inspired many patient, quiet workers in our great universities whose less known discoveries have not attracted the public interest, because they are aware that it is only through the hard work of the many that success comes to the few.
I would like to use as illustrations one or two pieces of work with which I am familiar. It was my good fortune to be one of the group of workers in Toronto which has produced a practical culmination to a long series of studies on diabetes. Sufferers from this disease had an excess of sugar in their systems.
For a great many years physicians have believed that a diseased condition of the pancreas was responsible for diabetes mellitus.
This belief was based upon the experiments of von Mering and Minkowski who in 1889 observed that the complete removal of the pancreas produced a severe and fatal diabetes in dogs. Five years previous to this, Villiard and Amazon had tied the tubes leading from the pancreas and found that the animals did not become diabetic, but that the pancreas shrivelled up. Other investigators, using a microscope, found that certain cells of the pancreas—the islands of Langerhans—were not involved, but that it was the other cells which disappeared.
Minkowski was the first to conceive the idea that an extract of the minced pancreas injected into a diabetic dog might relieve the symptoms. Caparelli, Battistini and Vanni prepared extracts and reported favourable effects, but their results were not confirmed.
Schafer discovered that an extract of the thyroid gland taken through the mouth by certain sufferers from diseases of thyroid gland lead to remarkable and striking improvements. Other and cumulative discoveries were made by brilliant and patient investigators.
Getting Close to a Solution
IN 1912, E. L. Scott prepared alcoholic extracts of the 1 pancreas, and showed that these extracts sometimes relieved certain of the symptoms of diabetes in animals. Scott was not satisfied with the methods of estimating the percentage of sugar in the blood and consequently left the problem, which he had almost solved, in order to obtain more precise methods.
In 1913, Murlin prepared alkaline extracts of the pancreas and also of the small intestine, and demonstrated that they reduced the elevated blood sugar in diabetic dogs. However, he found that this result could be obtained by the administration of alkalis alone, and the investigation was abandoned. After the war Murlin resumed his investigations and found that the administration of perfusates of the pancreas was followed by an elevation of the respiratory quotient. Thus, he could restore to the diabetic animal some of its lost power of burning carbohydrates.
These last two mentioned investigators came very close to the solution of the difficulty but failure in both cases, particularly in that of Scott, was due to the fact that their extracts were so weak and consequently the effects produced were so small that methods were not as yet developed which would enable the results to be accurate'y measured.
With the benefit of this previously accumulated knowledge, the work on insulin was commenced about the middle of April, 1921, with Mr. Charles H. Best, in the department of physiology, University of Toronto.
We first succeeded in showing that the blood sugar of diabetic dogs could be reduced to its normal level by the administration of extracts made from the pancreas of dogs, in which the ducts had been tied from seven to ten weeks and in which all the cells save those of the islands had disappeared. Furthermore, the administration of these extracts rendered the diabetic animals sugar free, and caused a marked improvement in their clinical condition.
Laguesse had found that there were comparatively more islet cells in the pancreas of the new-born than the adult. Ibrahim was unable to obtain any conclusive evidence of the presence in the pancreas of the human fetus of the active substances which are poured into the intestine by the ducts till after the fourth month of intrauterine life. This led to a second idea, namely, that extract free from the ordinary deleterious substances could be prepared from the pancreas of unborn animals. The third type of extract was obtained by extracting the pancreas of fetal calves of under four months’ development.
The work progressed more rapidly because of the more readily available supply of material furnished from the fetal pancreas, and led to such an increase in our knowledge that we were soon able to extract the active principle with alcohol from the whole adult beef pancreas. This extract was tried with favourable results on three patients in the wards of the Toronto General Hospital.
The early extracts undoubtedly contained protein, and it was recognized that these must be removed before the extract could be used on man. Even the first extracts caused irritation and pain at the area at which they were injected and more general disturbances to the patient. The final purification of this product was a very long and tedious process and was only possible by the knowledge that had been gained by all the labours of those numberless investigators who had been studying the properties of protein.
Ten or fifteen years ago our knowledge of this subject was so incomplete that the result could only have been obtained by experiments carried out blindly on a hit and miss principle. Even when the method had been discovered, slight impurities in the chemicals used, slight changes in the amount of acid present, could not have been detected and the product obtained would have been uncertain in its action, possibly dangerous in its employment.
Research in medicine is specialized and, as in all organized walks of life, a division of labor is necessary. In consequence a division of labor in the field of insulin took place. At this stage of our investigation, the Connaught antitoxin laboratory, under the directorship of Profs. Fitzgerald and Defries, provided Mr. Best and Dr. Collip with the facilities for the manufacture of insulin. Prof. Duncan Graham, of the department of medicine, established means whereby Drs. Fletcher and Campbell could investigate its clinical value, and Prof. J. J. R. Macleod abandoned his work on anoxemia and turned almost his whole laboratory staff on the investigation of insulin.
Under his direction various problems were allotted to pairs of workers and an unparalleled amount of information was gained in a comparatively short time.
I have elaborated at considerable length the history of the development of insulin, because it exemplifies the fact that research is built on research. At the present time we have insulin, but we do not know the exact manner of its action. We know that the deficiency of insulin is the cause of diabetes, because when this deficiency is supplied, the symptoms are relieved, but we do not know the cause of the deficiency. We know that the insulin mechanism is related to other glands of internal secretion, particularly the suprarenals, but we are far from a complete knowledge of their interaction, without which a complete understanding of the disease cannot be attained.
Diabetes is not solved. The pathological findings do not bear an exact relationship to the clinical severity of the case.
Recently Dr. Joslin of Boston sent the pancreas of a patient who died in diabetic coma to Mr. Best, who was able to extract from it abundant insulin. Mann has found that the removal of liver in dogs is followed by a rapid and extensive fall in the percentage of sugar in the blood. The extract of the little-known pituitary gland in the brain augments the action of insulin. Mr. Best has been able to extract insulin from the tissues of every organ of the animal body. Woodyatt and others have injected very large quantities of sugar into animals and cannot adequately explain its disappearance.
These and other unexplained problems challenge the research worker in carbohydrate digestion at the present moment. Their explanation is necessary before diabetes can be explained and its cause known.
The use of insulin has spread rapidly throughout the world. It is believed that it was employed in the treatment of 40,000 cases of diabetes last year in the United States alone. It is now being manufactured in at least ten different countries, and soon we hope that it will be within the reach of every diabetic who requires it.
Other Epochal Discoveries
One might collect numerous other cases where in the world of science this gradual building up of knowledge led to valuable results. I will quote one or two examples because they happen to be well known to me and have occurred in the university within recent years, and consequently I know something of the facts at first hand.
Nitrous oxide was discovered by Lavoisier in France and by Priestley in England about the end of the eighteenth century. In 1800 Humphrey Davy discovered that if he breathed this gas he became intoxicated and anaesthetized. This peculiar intoxication, so harmless and so transitory, was frequently employed as a demonstration at popular lectures. It was as a result of such a popular lecture in Hartford, Connecticut, in 1884, that Horace Wells, a dentist, used it as an anaesthetic for the drawing of a tooth, and in 1846 it was used for the first time for a surgical operation. But nitrous oxide, if taken pure, prevents the patient from getting oxygen and in consequence he would die of suffocation, if he continued to breathe it for more than three or four minutes, and no great progress was made until Andrews in 1868 showed that using a suitable machine the gas could be mixed with small amounts of oxygen and therefore taken for much longer time. Before such a gas could be transported in quantities it had to be compressed. This took many years of research. Further, when compressed into iron cylinders it is under great pressure and this must be reduced before it can be given to the patient without great loss. Here, too, much ingenuity and skill was required. The development of the necessary machines which makes its employment possible in the thousands of operations which take place to-day under this relatively harmless anaesthetic, was due to the labors of physicists and of mechanical engineers.
All the work and study which has led to the perfecting of methods by which nitrous oxide can be given as an anaesthetic and which have just reached the point where it is a practical procedure for general employment have also made possible the practical application of other gases which can be compressed. Many years ago, in 1885, Sir Benjamin Ward Richardson took a great many gases and tested their anaesthetic properties on animals. Amongst those mentioned by him were such gases as methane and ethylene. There was no method in his day of making practical use of his findings and they were almost completely forgotten until Dr. W. Easson Brown in Toronto, simultaneously with Drs. Luckhardt and Carter in Chicago, were able to show that ethylene was a most useful anaesthetic gas apparently as harmless as nitrous oxide, and having the great advantage that it could be given with such a large quantity of oxygen that the patient was not suffocated at all. This anaesthetic is being widely employed in the United States. But Dr. Brown has recently described a more potent gas which if it can be produced economically would undoubtedly be better even than ethylene.
Here again knowledge gained one hundred years ago and which seemed for a full half century to be little else than a scientific curiosity has become one of the greatest weapons in the hands of the surgeons and, as the war showed conclusively, thousands of persons have survived the dangers of anaesthesia owing to the use of nitrous oxide, and there is promise that the advent of these newer gases may even still further reduce the danger.
Another interesting example in a purely technical field which has awakened a great deal of interest in scientific circles, but which has not as yet reached its full practical application, is the study carried on by Professor J. T. Haultain and Professor F. C. Dyer on the motion of balls in a ball mill.
The ball mill seems long to have been used for the grinding of drugs to fine powder and for this purpose a very simple form is used. This form consists of a porcelain jar with a tight-fitting cover. It is rotated on its long axis. In this jar (or barrel) is placed the drug and either iron balls or quartz pebbles. When the mill is rotated the balls gradually wear the drug down to a powder. About 1890 the ball mill was first used in the manufacture of cement and some ten years later it was first employed for grinding ore to powder in order that the gold contained in it might be extracted.
But no one knew how the balls really did their work until Professor Haultain managed to set up a mill with a glass face and take moving pictures of their motion. These pictures are reproduced slowly and the exact motion of the balls can be studied. These pictures have been shown in the United States, Australia, South Africa, and have awakened lively interest, and will undoptedly lead to a still further development of this mill which has already proved so valuable to the miner and cement manufacturer.
The great mill of science grinds slowly but surely. Bit by bit the hard secrets of nature are broken into, and the pure metal revealed. Those who are contributing to these problems are often appalled at its apparent slowness and long for the day when a bigger forward step can be taken, yet all the readers of this article are aware of the tremendous advances that have taken place in our daily lives owing to the progress of science.
Progress is only possible when certain conditions are fulfilled. First one must have the men. Universities and other institutions which are to provide the scientific advances for material development must be able to attract and hold men of original minds and of working capacity. Further, these men must have the wherewithal to carry on their work. They must not be made to feel that too great things are expected of them; that great discoveries must come every year; but they must also realize that they must work faithfully and thoughtfully to advance our knowledge and must inspire others to follow in their footsteps. It is in this respect that a great university has an advantage over a small one.
As Professor Lash Miller once put it: “The University of Toronto has now become a mechanism, the separate little cog wheels are beginning to interlock, cooperation has become possible.”
It is rarely that a technical or scientific difficulty arises in the work of any investigator where in his perplexity he cannot go to some other men of the staff and find one who can give valuable assistance. No branch of science to-day is isolated. The physiologist is employing apparatus devised for wireless telephony, the pharmacologist employs the devices of the physicist and relies on the tricks of the chemist. The chemist in turn must be a physicist and the physicist must know something of chemistry and on the border lines between the sciences where progress so frequently occurs, co-operation and assistance must take place. Without such co-operation of many men with varied, knowledge the discovery and manufacture of insulin would have been impossible, surgical operations would be full of the terrors they possessed in the time of our grandfathers and the extraction of gold from many ores impossible. Canadians must support research in many fields in order that the world may become a better place in which we and our children may live.
Problems Facing Canadians
The fields of research for the development of our vast country are manifold. For the health of our peoples many medical problems must be solved. The man of business will suggest that for our pleasure and well-being many economic difficulties must be overcome, but he does not always stop to think to how great an extent economic possibilities are dependent on the advance of fundamental problems of science and of medicine. The Panama canal was not built by the French, because the cost in lives was too great owing to . the lack of medical knowledge, that then existed. The Americans built the canal because they knew how to control disease.
Let us consider various problems, some of them particularly Canadian, at which Canadians are working and whose solution might mean much to Canada and often to the world at large.
In the great western provinces and in British Columbia there are many alkaline or salt lakes. For hundreds of years from their waters salts have been deposited. Our Government has investigated some of these deposits. Our industrialists have begun to use them but not with the desired profit or success. Some of these lake deposits contain very large quantities of Glauber’s Salts, sodium sulphate. This material is used in large quantities in our pulp industries. It is relatively cheap in the crude form at present, but there are prospects that the price will rise and we will all pay for it in dearer paper. In the West we have great quantities. Can it be marketed at a reasonable profit? Glauber’s salts in crystals contain a great deal of water. Could this water be expelled and the salt shipped dry, the freights would be less and it could be sold. How can the water be removed? This is a problem for the pure chemist. The unknown hardworking researcher must tell us more about this water and the conditions under which it can be removed and the chemical engineer must apply the knowledge thus acquired to a big industry. Canadians are working on these problems; let us watch for their success.
In another field a problem occurs where Canadians in our more western province are leading the way. Everybody has read in the street-car advertisements of Cascara. This purgative is much favoured by physicians. It is prepared from the bark of a tree which grows in British Columbia. There is a belief that it can be obtained only from the bark, and only if the bark is cured for three years. The world’s supply is not abundant, the price relatively high, yet the active substances occur, as Canadian workers have shown, in the wood. If the drug can be obtained from the wood, the world’s supply is increased to the advantage of us all. Its preparation is a chemical problem in which physicians must aid.
During the war the allies found that they were handicapped because Germany had had almost a monopoly in the production of dyes and new medicinal chemicals. Great Britain and the United States have learnt their lesson and are building up a dye industry and a medicinal chemical industry. Why should Canada not help? Already Canadian chemists have invented new dyes and their work should be encouraged. Dyes are expensive things. We all wear them. Why should we not add to the richness of the world in this field also?
Diabetes has been robbed of its horrors. A serious attack has been made on scarlet fever. There is another dread disease whose course and onset suggests that it is a fair target that it may fall before the attack of trained medicine ere long. This is pernicious anaemia, a slow death, a year long sapping of strength and energy. There are probably thousands of cases in Canada. Patient Canadian research workers, to my personal knowledge, are working at its causation. Let us pray that they may be successful and that another scourge may be removed.
Let us again revert to the West. In our great plains the waters are alkaline as many visitors to Winnipeg have learned. These alkalines enter the water from the soil. Cement exposed to the action of such water quickly “rots,” to use a common phrase. Roads and house foundations suffer. This is a chemical problem. If we knew the chemical cause a cure might be, probably would be, discovered. Here, too, chemists in Canada are at work and as in the other problems more workers would be aiding the feeble efforts now being made were the means available.
Suppose we meet the economist or ask him to meet us. A million dollars worth of insulin was sold last year. Were ten per cent, of the profits turned into a research fund it would support several workers. Estimate the lives saved. The Metropolitan Life Association calculates that the deaths from diabetes in insured cases fell thirteen per cent, last year lower than expectation, and they fell more in Canada than elsewhere. Suppose of the 4,000 cases 10,000 are of real value to the world and their lives are prolonged for ten years, each at a value to the nation of $1,000 each per annum, $10,000,000. A fraction of this sum would help to solve many medical problems.
The discovery of Marquis wheat is said to have added $100,000,000 annually to the value of the wheat crops of Canada: certainly enough to have justified the Government in adequately providing for its discoverer during his life time instead of giving him merely a pittance when he retired—-and enough to have paid for all our schools of agriculture several times over.
Research gives us health, wealth and happiness but also too often we do not realize from where these good things come.
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