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In the Footsteps of Pioneers

On Tuesday, May 14, 1912 the graduating class of the University of Alberta assembled for the first formal convocation ceremony of the fledgling university. A year earlier graduation ceremonies had been held for a handful of students, but the Class of '12 was the UniversityÌs first authentic graduating class and the convocation reflected that.

For the University it was a coming-of-age of sorts, and in a robust spirit the institution set about fulfilling plans for expansion — a buoyant faith in the future of the young province naturally leading to the creation of professional schools. Law had its beginning in 1912, and applied sciences was given its own life the following year. And in that same year, 1913, the Faculty of Medicine came into existence as the fourth faculty of the University, offering a three-year course of basic instruction which preceded a final two clinical years elsewhere.

The early interest in medicine at the University of Alberta is understandable, given not only the expressed need for physicians to serve the rural areas of the province (how little things change!) but the early involvement of members of the medical profession in the life of the University. Prior to the opening of the University in 1908, all graduates of Canadian or British universities who were resident in Alberta were invited to register as members of convocation. Convocation as thus instituted consisted of 364 members —104 of them, medical doctors.

When the University of Alberta introduced medical instruction in 1913, there were seven medical schools in Canada, but none west of Winnipeg. Records show that 26 students constituted the University of Alberta's first class in medicine and that "arrangements were perfected to carry them through at least three years of a five-year course with the privilege of being transferred, if necessary, with full standing to certain eastern universities." During the period 1913 to 1922 about 150 students completed the three-year program in basic medical sciences and were admitted with advanced standing to McGill, Toronto or Manitoba.

In 1920 the Rockefeller Foundation made a gift of $100 million for the improvement of medical education in the United States and Canada. Of this, the University of Alberta received $500,000, which generated an annual income of $25,000 — a not inconsiderable sum at the time. The donation coincided perfectly with the University's move to offer the final clinical years of the MD program; the Rockefeller income helping to pay the added teaching staff necessary.

The first class to receive MD degrees from the University of Alberta convocated in 1925. Many would follow them. Graduation statistics show that 3,387 persons have to date received MD degrees from the UniversityÌs Faculty of Medicine. The Faculty has also awarded the degree of Bachelor of Sciences in Medicine 360 times and the Bachelor of Medical Sciences degree on 906 occasions.

The years of the Great Depression and the Second World War left their marks on the history of the Faculty, but it was not until the end of the War that the next major development in the life of the Faculty occurred — the expansion in research. There had, of course, been research conducted previously; some of it quite significant (in his history of the Faculty of Medicine published in 1963, John W. Scott singles out R. F. Shaner's important research on the embryology of the heart; the work of A.W. Downs and N.B. Eddy in physiology and pharmacology; the valuable research in anesthesia conducted by Samuel Gelfan who, with I. R. Bell, was first to use divinyl ether as an anesthetic on human subjects; and the very major contributions of biochemist James B. Collip) but it was in the quarter century beginning in 1946 that medical research came into its own at the University of Alberta. This period saw the introduction of graduate programs, a sizeable increase in the number of full-time faculty members, and a concomitant blossoming of research.

While the '70s and '80s have brought their changes — not the least evident being the remarkable improvement in physical facilities-research, along with teaching and public service, remains a mainstay of the Faculty of Medicine as it enters its 76th year. While some of this research heads in directions undreamed of in earlier years, a surprising amount follows firmly in the footsteps of the FacultyÌs research pioneers. In the remainder of this article, we will follow two of the threads that connect some of the earliest medical research undertaken at the University with some of the most up-to-date.

The Calcium Connection

Of the scores of minerals essential to the proper functioning of the human body, few play as broad a role as does calcium. While we may be most apt to associate this mineral with strong bones and teeth ("Now don't forget to drink your milk!") calcium, in particular ionized calcium, is vitally important to a large number of body processes. These include coagulation of blood, activation of enzymes, maintenance of the integrity of cell membranes, and the functioning of the nerves, muscles and heart.

In keeping with this importance to life processes, the body regulates few ions more diligently than it does calcium. The concentration of ionized calcium in blood and tissues is maintained within a very narrow range by an elaborate system of checks and balances. This regulation involves, among other things, Vitamin D, calcitonin, and the hormone secreted by the parathyroid gland.

From its early days the University of Alberta has had researchers interested in calcium metabolism. Dr. James Collip, the first chairman of the University's biochemistry department, was, in 1925, the first to successfully extract the active principle from the parathyroid glands. Today, a University of Alberta team including Dr. Chuck Harley ('65 MD) and Dr. Tom Overton, a medical physicist who studied at Leeds University, are investigating another important aspect of calcium metabolism related to the bone: the development of osteoporosis in elderly women and, in particular, the measurement of bone mass using computer tomography.

Dr. Collip, who initiated the interest in calcium studies at the University, was born in Belleville, Ontario in 1892. In 1907 (only 15 years old) he entered Trinity College of the University of Toronto in a new honors program in physiology and chemistry. By 1916 he had received his doctorate in biochemistry and joined the fledgling Faculty of Medicine at the University of Alberta. His laboratory facilities in the UniversityÌs Old Power Plant may have been rather primitive, but the following year he published an important review article on what was then a relatively new field — internal secretions — in the Canadian Medical Association Journal.

Five years later, in 1921, he took a sabbatical leave funded by a Rockefeller Travelling Fellowship and returned to the University of Toronto. In the fall of that year he was invited by Banting, via Macleod (the professor of biochemistry), to work on the Toronto team engaged in the study of insulin. When Collip arrived Banting and his team had only a crude, uncertain pancreatic extract with which to work; in a remarkably short time the University of Alberta biochemist had refined the technique of insulin extraction to such a degree that the extract could be used in the first human patients. (Eventually the process was patented in the names of the three principal researchers — Banting, Macleod and Best — and given to the University of Toronto.)

As a result of this collaborative work on the discovery of insulin, Banting and Macleod were awarded the Nobel Prize. In accepting, Banting shared his Prize with Best, and Macleod shared his with Collip. There was considerable personal friction among the group, however, and Collip returned to the University of Alberta, where he was appointed chairman of the new biochemistry department. (Fuelled by this friction, controversy about the exact contributions made by each of the members of the insulin team thrived and continues to this day.)

Upon returning to Alberta, Collip initially dedicated himself to work with glucokinin, a plant hormonal product with apparent hypoglycemic properties in animals ç the hope was that this would be a vegetable-based alternative to insulin. However, at the same time he was working on extracting the active principle from the parathyroid glands.

In 1925 Collip published his successful method of extracting parathyroid hormone, which he named parathormone, and the University of AlbertaÌs Dentistry/Pharmacy Centre (then the Medical Building) was the site of the first injection ever of purified parathyroid hormone. Not only would this hormone control tetany — a condition involving muscle spasms due to abnormal calcium metabolism — in dogs from which the parathyroid glands had been removed, it could cause high blood calcium rates in such dogs, as it would in normal dogs, if given too frequently or in excess. Collip subsequently wrote in one of his publications that "it is possible that this hormone will have many practical uses." He went on to say, "Calcium metabolism enters into many medical problems." (Perhaps more than even he dreamt of!)

In 1929, four years after publishing his milestone parathormone paper, Collip left Alberta to go to McGill where he remained until 1947, at which time he became dean of the medical faculty of the University of Western Ontario, serving there until 1961. He died in 1965, after an effective, productive career, and has considerable claim to be considered the outstanding Canadian biochemist. In fact, when the Alberta Medical Association put together a history of Collip, it described him as "Canada's most distinguished medical scientist of the 20th century."

Following in Collip's footsteps are Harley and Overton, whose interest in calcium metabolism relates to bone. Bones are, of course, fundamental to the body — they are its framework and its levers, they protect our internal organs, and they are reservoirs for essential minerals (calcium prominent among these). In particular todayÌs researchers are concerned with osteoporosis — that post-menopausal, age-related bone degeneration long considered to be an inevitable and untreatable concomitant to aging, leading to the stereotypical picture of the "little, hump-backed old lady."

Osteoporosis is a serious and major problem of the elderly, and increasingly so as the population of Alberta (and Canada) is aging. Current estimates are that 12 per cent of the population will be 65 years of age or older by the year 2000. (It should be noted that despite the strong association with the elderly, osteoporosis is not limited to the aged. The term osteoporosis was first used to describe the reduced bone density evident on a radiograph — x-ray picture — and is now used in a broader sense to describe the generalized reduction in bone density resulting from a wide variety of causes, not all age-related.)

In the past, qualitative estimates of the degree of osteoporosis were made on the basis of the bone density in plain radiographs of the skeleton. As some 30 to 50 per cent of bone mass must be lost before the loss is evident on plain x-rays, it is obvious that such evaluations are not of much use in the early detection of bone loss. While various quantitative methods have been employed to give earlier detection, today the most useful and preferred method is computed tomography (CT Scan), as it has the capacity to evaluate both cortical (outer edge) and compact (structural) bone at various skeletal sites with sufficient precision to monitor the bone mass over time, in health and disease, without painful injection or the use of radioactive isotopes.

As a result of studies by Harley, Overton and their colleagues around the world, a much clearer understanding of the dynamic nature of the skeleton has emerged, especially relating to the nature and functioning of trabecular bone (the marrow bone). It is now recognized that there is a constant remod-elling process taking place which replaces old (probably damaged) bone with new bone over about a four-month period. During the remodelling, bone is first resorbed by multinucleate giant cells (called osteoclasts), there is then a reversal phase, succeeded in turn by bone matrix reformation (by bone cells called osteoblasts), and this is followed by remineralizing of the newly formed bone. This entire process is spread over a period of approximately 100 to 120 days.

The evidence is that normal mechanical use of bone in everyday activity accumulates microdamage to the bone interior, and this acts as one trigger for the remodelling process. Present research is examining the effects of Vitamin D, calcium and other minerals, and hormones in protecting the bone against ravages of age which result in severe and crippling osteoporosis. While this work may seem far removed from the experiments carried out so many years ago in the University Power Plant and later the Medical Building, the fact remains that the advances in knowledge today are firmly rooted in discoveries made more than 60 years ago by James Collip.

A Journey of the Heart

In its frequently quiet and understated manner, the University of Alberta has been a leader in affairs of the heart for more than 60 years. From pioneering work which provided the most basic of information about heart function and disease to the modern-day wizardry of heart transplants, the Faculty of Medicine has had a journey of the heart well worth recording.

The first great milestone on that journey is the coming to Alberta in 1921 of Ralph Shaner, professor of anatomy. Shaner, a Harvard graduate, had been recruited from Harvard by Henry Marshall Tory himself. The new anatomy professor soon showed himself to be another example of the first presidentÌs talent for finding the right person for the job.

Shaner quickly became identified as a superb teacher, one of the best that the anatomy department ever had, and taught every medical student who graduated with an MD from 1921 until the mid-'60s. He was also dedicated to his research, which centred on the embryology of the heart — how did the heart develop and how and when did it go awry to produce defects which might range from inconsequential to fatal? He pursued these questions with the assistance of Alberta farmers, and students in anatomy will recall the many glass bottles containing pickled pig hearts collected from rural communities around Edmonton. It has been estimated that Shaner did something like 50,000 pig embryo dissections over the years.

Shaner's world class research contributed enormously to the understanding of cardiac defects. It also provided a background for the development of clinical cardiology in Edmonton hospitals.

Close to the time that Professor Shaner was retiring, Dr. John Scott, emeritus dean of the Faculty of Medicine, published a book describing the first 50 years of the Faculty. In the book he speculates on the next 50 years and asks of the year 2013 (the Faculty's centenary): "Will our knowledge of immunology and the perfection of surgical skills have reached a point where transplantation of organs and limbs will be an everyday procedure in the operating room?" In fact, recruitment under Dr. Scott's leadership was already paving the way for that time, and fewer than five years after he posed his question, kidney transplants were becoming routine in the University Hospital.

Some years before Scott pondered the mysteries of the future, another milestone in the Faculty's journey occurred. In 1953 Robert Fraser ('44 BSc, '46 MD, '50 MSc), later to become chairman of the department of medicine, returned to his alma mater to join Joe Dvorkin ('41 BA, '43 MD) in establishing Alberta's first laboratory for invasive cardiology investigation. They gained information about their patients by inserting catheters into the heart along a vein from the groin or other access point. The procedure was relatively new and certainly dangerous. Without it, however, diagnosis for surgically repairable lesions was tenuous and unreliable.

By 1956, Dr. John Callaghan — who thirty years later would be awarded the Order of Canada for his contributions to this country — had assembled his surgical and research team at the University. In the fall of that year the team members made headlines when they performed their first open heart surgery. In December of the same year they performed the first "blue baby" operation in Canada to repair cross-circulation problems in the heart of 18-month old Sherry Anderson, who now lives in British Columbia and has her own family.

In March of 1986, Callaghan's team celebrated open heart operation number 7,000. Conditions then were vastly improved from those of the '50s. In those early years much basic research related to the anatomy of the heart defects remained to be done, and there were many technical problems associated with both the surgery itself and the heartlung machines. In addition, puzzles related to the metabolic support of the patients had to be solved.

The base of knowledge grew rapidly, however, and as it did the cardiology and cardiac surgery groups grew in size and sophistication. From the primitive equipment acquired or jury-rigged by Fraser and Dvorkin to the relative sophistication of the present day has indeed been a multi-generation leap.

The ability to quickly and accurately measure pressure inside the various chambers of the heart, to monitor oxygen saturation and the electrical conductance pattern, and to image the heart, its walls, valves and arteries by multiple means has laid the groundwork for the most recent step: Dennis Modry ('71 BSc, '73 MD), who had trained at Stanford University, which has the world's most successful heart transplant program, convinced the University Hospital and the Alberta government of the soundness of a heart transplant program, and in 1986 Modry's team conducted the first such operation ever done in western Canada.

That historic surgery took place fewer than 25 years after Scott's gaze into the future. As the former dean so appropriately identified, understanding of the immune system and new drugs to control immune activity had to go hand-in-hand with surgical advances. The development of immunosuppressant drugs to keep transplanted organs alive and functioning in a totally normal fashion is the other side of the heart transplant story. But that's another journey.

The authors are senior members of the University's medical faculty. Dr. Adrian Jones, '63 MD, who traced the journey of the heart, is a professor of pediatrics and serves as the Faculty of Medicine's associate dean (faculty affairs). Dr. Gerald Higgins, a Bristol graduate who serves as the FacultyÌs chairman of community medicine, followed the calcium connection.

Published Spring 1988.

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