April 24, 2017History of Medicine
Fuller Albright's remarkable book Parathyroid Glands and Metabolic Bone Disease, a landmark publication in 1948, summarized Albright's many contributions to mineral metabolism during the previous two decades.
Fuller Albright was born in Buffalo, New York, on January 12, 1900. His father was a wealthy industrialist and philanthropist. The major art museum in Buffalo is known today as the Albright-Knox Art Gallery. Albright attended the Nichols School in Buffalo, which was founded by his father. He not only excelled academically, but also was captain of the football team. During his childhood, the Albright family made frequent visits to Wilmurt Lake in the Adirondacks, where he became an avid fly fisherman and developed woodsman's skills. During his academic years in Boston, Albright would spend summer vacations at Wilmurt Lake with his family. It was at Wilmurt Lake where he directed that his ashes be scattered after his death.
Fuller Albright attended Harvard College, but after only 18 months, he falsified his age and enlisted in the Army after America's entry into World War I. It was also the time of the great influenza pandemic, which has been postulated to be a cause of Parkinson's disease many years after recovery from influenza. Albright was to develop Parkinson's disease in his mid-30s, and it was to progress relentlessly during the next two decades of his life. In 1921, Albright entered Harvard Medical School, where he excelled and was elected to Alpha Omega Alpha. On graduation, he did an internship and residency in Medicine at Massachusetts General Hospital. There he met Read Ellsworth, who became a close friend and collaborator. Both initially were mentored by Dr. Joseph Aub, a clinical scientist in endocrinology and metabolism. Albright and Ellsworth continued their research collaboration in mineral metabolism until the latter's premature death from tuberculosis in 1937. Perhaps the most critical year in Albright's training was that of 1928-1929, when he went to Vienna to study with Dr. Jacob Erdheim, a brilliant pathologist who in 1906 had established the relation between the parathyroid glands and calcium metabolism by showing that calcium is not deposited into growing teeth in the absence of parathyroid glands. Also, it was Erdheim who had first described compensatory hyperplasia of the parathyroid gland associated with osteomalacia. Albright often would later say of Erdheim that quite simply he knew more about human disease than any other living man and referred to him as the greatest of living pathologists.
Albright returned to Massachusetts General Hospital in 1929. There he would begin his long, productive career in clinical research, much of which emanated from the then recently established Ward 4, which was a 10-bed research unit where patients and healthy subjects could be intensively studied. On Ward 4, special diets could be prepared, biochemical measurements could be performed, and meticulous collections of urinary and fecal output could be obtained. The latter, when combined with measurement of dietary intake, constituted the balance study that became a major investigative tool for Albright. Albright married Claire Birge in 1932, and they had two sons. She became a major source of support for him as his Parkinson's disease progressed. By the early 1940s, Albright could no longer write, and by the mid-1940s his speech had become difficult to understand. In an article written in 1946 for the twenty-fifth anniversary of his medical school class enrollment, Albright wrote, I have had the interesting experience of observing the course of Parkinson's syndrome on myself. It disturbs every movement and gives a certain rigidity that makes small talk look strained. The condition does have its compensations: one is not taken away from interesting work to be sent to Burma, one avoids all forms of deadly committee meetings, etc.
The patients for Albright's studies came from his three weekly clinics: the Ovarian Dysfunction Clinic on Tuesdays, the Stone Clinic on Wednesdays (also known as the Quarry), and the general Endocrine Clinic on Saturdays. Even when not involved in a study, every patient would return to the respective clinic at least once per year. If a patient failed to return, a visiting nurse would be sent to find the patient. In 1939, Anne Forbes became his physician administrative chief and collaborator. She assumed much of the administrative and organizational burden for his studies. In 1942, Albright became an Associate Professor of Medicine at Harvard, but not wanting any administrative burden, he refused to become a full professor. In the 1950s, the medical student taking an elective with Albright would be given the family's second car with the assigned task of transporting Albright to the hospital and looking after him at work. These students included such future well-known investigators as Howard Rasmussen, James Wyngaarden, Steven Krane, Kurt Isselbacher, and Stan Franklin. By the early 1950s, Anne Forbes has said that Albright was convinced that the Parkinson's disease was affecting his intellect. In 1952, a noted New York neurosurgeon, Dr. Irving Cooper, had reported that Parkinson's patients could be improved by a surgical procedure, chemopallidectomy, in which small amounts of alcohol were injected into the areas of the brain responsible for the tremor and rigidity. Despite expert advice to the contrary from his Harvard colleagues and even from Dr. Cooper, Albright was determined to undergo the procedure because of his inability to speak comprehensively and a severely impaired capacity to dress, eat, and write. The surgery was performed in June 1956. After the intervention on the right side, a marked improvement in symptoms was observed. However, the operation on the left side was followed by a major cerebral hemorrhage, from which Albright would never recover. For the next 13 years, he lived in a vegetative state. In a ceremony in 1961, Fuller Albright was officially retired from the Faculty of Medicine at Harvard as Professor, Emeritus. Fuller Albright died on December 8, 1969.
Albright, the Clinical Investigator Par Excellence
Albright's work on serum calcium and phosphorus regulation, primary hyperparathyroidism, and the renal excretion of calcium and phosphorus became the foundation of our understanding of mineral metabolism. His description and study of vitamin D resistant rickets became the basis for the study of renal phosphate transport. Starting in the late 1920s and continuing through the mid-1930s, Albright's primary focus was studying how differences in dietary calcium and phosphate affected calcium and phosphate balance in healthy subjects and in patients with primary hyperparathyroidism and with hypoparathyroidism. Healthy subjects and patients with hypoparathyroidism were studied with the newly available parathyroid extract (PTE). Because the balance studies were remarkably consistent, only a small number of subjects needed to be studied to provide the results, which remain true today. Albright was the first to provide a comprehensive framework for understanding the regulation of calcium and phosphate in normal subjects and in patients with parathyroid disorders. The report of the seventeen patients operated on for primary hyperparathyroidism published by Albright in 1934 was the largest series until then. The number of patients in that series diagnosed with primary hyperparathyroidism had been greatly expanded when Albright had the insight to measure serum calcium values in patients with kidney stones. At diagnosis, primary hyperparathyroidism was a much more severe disease than now. The average preoperative serum calcium value was 13.9 mg/dl and the average weight of the removed parathyroid adenoma was >11 g. Parathyroidectomy was an entirely new operation for surgeons and required intensive training with autopsy material. Two remarkable findings characterized the first 17 parathyroidectomies. Two patients had ectopic locations of their parathyroid adenoma, one of whom was the famous Captain Martell, who required seven operations before the ectopic gland was discovered. Cases 15 through 17 had parathyroid hyperplasia and not an adenoma as the cause of the hyperparathyroidism.
In a discussion of a case of renal osteitis fibrosa cystica in 1937, Albright suggested that the reason for parathyroid hyperplasia was the phosphate retention in renal failure. He added that in the absence of parathyroid hyperplasia, there would be greater phosphate retention and a further lowering of the blood calcium. Also in 1937, Albright described a patient with rickets that was resistant to treatment with vitamin D. This patient was intensively studied and clearly differentiated from patients with rickets from vitamin D deficiency. The name given to the disorder by Albright, vitamin D resistant rickets, was in use for many years until it was renamed X-linked hypophosphatemic rickets. This disorder also became the basis for the study of abnormal renal phosphate transport. Finally, in 1937, Albright reported five cases of another unusual bone disorder, polyostotic fibrous dysplasia, which was associated with hyperpigmented lesions of the skin and endocrine dysfunction. Today the disorder is called the McCune-Albright syndrome. In 1941 at a clinicopathological conference, Albright asked why a patient presenting with a destructive bone lesion in the right ilium from renal cell carcinoma should have hypercalcemia and hypophosphatemia. A neck exploration for presumed hyperparathyroidism was performed, but no abnormality was found. Albright questioned whether the tumor might be responsible for ectopic production of parathyroid hormone. In the same year, Albright described a case of hypercalcemia in a 14 year old boy who fractured his femur through a bone cyst in an athletic accident. After casting and bed rest, the patient developed severe hypercalcemia. Because of the hypercalcemia and the presence of a bone cyst, a parathyroid exploration was performed but no abnormalities were seen. Albright was the first to recognize that immobilization could cause hypercalcemia. A similar report of hypercalcemia following immobilization in Paget's disease was published in 1944. In 1942 Albright described pseudohypoparathyroidism. In this disorder, the important concept of end-organ resistance to a hormone (PTH) was first shown. Albright chose the name, Seabright-Bantam, because this male fowl has feathers similar to the female despite having normal functioning testes. Other highlights of Albright's investigation into disorders of calcium and phosphorus included his publication in 1946 of osteomalacia, rickets, and nephrocalcinosis in association with renal tubular acidosis. In 1948, Albright reported the occurrence of band keratopathy of the cornea in 19 patients with diverse causes of hypercalcemia. In 1949, Albright reported several patients with the chronic form of the milk alkali syndrome. These patients had chronic renal failure, hypercalcemia, soft tissue calcium deposits, band keratopathy, and nephrocalcinosis from the chronic ingestion of calcium- containing antacids. In 1953, Albright reported 35 patients with idiopathic hypercalciuria associated with kidney stones, hypophosphatemia, and normal serum calcium values.
Pituitary, Adrenal and Gonadal Axis
While much of Albright's first decade as a clinical investigator was devoted to studies of mineral metabolism and the diagnosis and treatment of primary hyperparathyroidism, studies of adrenal and gonadal disorders assumed greater importance in the 1940s. His elegant studies of the Cushing syndrome were highlighted in three papers published in 1941. These studies were previously reviewed in detail by Schwartz, but will be summarized here. In the first paper, Albright showed that glucose intolerance and resistance to insulin were characteristic findings of the Cushing syndrome. In the second paper, Albright showed that besides cortisol excess, the Cushing syndrome was also characterized by androgen excess. The 24 h urine excretion of 17-ketosteroids was used as a measure of androgens. Because urinary excretion of 17-ketosteroids was greater in men than in women (14 versus 9 mg), Albright reasoned that 9 mg was the daily androgen output from the adrenals. His hypothesis was confirmed by studying patients with Addison's disease in whom the excretion of 17-ketosteroids was 5 mg in men and absent in women. Albright also showed that adrenal excess was the cause of all forms of the Cushing syndrome whether of primary adrenal origin or due to a pituitary adenoma. In the third paper, Albright treated patients with the Cushing syndrome with testosterone, asking the question whether such treatment would counteract the catabolic effects seen in this syndrome. The testosterone treatment resulted in a strikingly positive nitrogen balance, a gain in weight and strength, thickening of the skin, and a reduction in abdominal protuberance. However, because of the availability of adrenal surgery, the use of testosterone treatment never gained widespread use. Albright also performed several studies that helped elucidate the etiology of congenital adrenal hyperplasia, which was called the adrenogenital syndrome by Albright. The paper in which Klinefelter's syndrome was first described was published in 1942. The story is that the syndrome was discovered because the Draft Board in Boston sent recruits with prominent breasts to Albright's clinic where small testes were noted and biopsied, and follicle stimulating hormone (FSH) levels were measured and found to be increased. Also in 1942, Albright further defined Turner's syndrome by showing it was not of pituitary origin, but rather due to primary ovarian failure in which elevated FSH values were present. Finally, it has been stated that Albright first described or contributed to the description of 14 major clinical syndromes.
Albright, Through the Eyes of Coworkers and his Presidential Address
Fuller Albright's 1944 presidential address to the annual meeting of the American Society for Clinical Investigation, Some of the Do's and Do-Not's in Clinical Investigation, is important because in it he provides his personal road map for performing clinical and laboratory investigation. In his introduction, Albright states that the clinical investigator must avoid the danger that he or she, as the clinician, be swamped with patients and the equal danger that he or she, as an investigator, be segregated entirely from the bedside. Even though his advice to the investigator is shown as a road map leading to the Castle Of Success (Figure 1), Albright refuses to define success, except to say that it is more than academic recognition and self-satisfaction. The reader is strongly encouraged to read this remarkable address in which Albright provides the investigator with the gift of his wisdom. It is readily available in the archives of the Journal of Clinical Investigation.
The following colleagues' appreciations from several physicians who worked with Albright, are cited: William Parson worked with Albright during the late 1930s and early 1940s and later became Chairman of Medicine at the University of Virginia. In 1995, Parson wrote of Albright's creative genius and his engaging personal qualities of unpretentiousness, good humor and wit. He went on to say that Albright was the first to conceptualize two important concepts in Endocrinology, end-organ unresponsiveness to a hormone (pseudohypoparathyroidism) and hormone or hormone-like production by nonendocrine tissue (ectopic production). Parson continued, Albright never had an interest in bench work. He felt that he could always get someone to make the measurements. The trick was to know what to measure and how to interpret the results. It was fun and exciting to work with a genius whose talent was to see relationships between facts universally considered to be unrelated. During the study of the first patient with pseudohypoparathyroidism, Parson relates that Albright was intrigued by her unusual appearance and the failure of a good batch of parathyroid extract to work. Albright refused to move on, even though others wanted to substitute dihydrotachysterol treatment and drop the project. Frederic Bartter worked with Albright in the 1940s and later became Chief of Clinical Endocrinology at the NIH. After Albright's death in 1969, Bartter wrote a homage to Albright in which he said of Albright that clinical experiments of nature were the substrate for almost all of the inspired and systematic investigation that constituted his enormous contribution. He continued that Albright's real delight was in formulating a theory to explain the unknown elements that remained, and Albright had no use for the learned tradition. Rather, Albright believed that progress could only be made by formulation of a precise theory and challenge of that theory. Finally, Gilbert Gordan, who did a fellowship with Albright in the late 1940s and later became Professor of Medicine at the University of California at San Francisco, wrote in 1981 that when Albright was working on a problem he virtually lived it every day, and he would discuss his ideas with anyone who was interested. Albright was completely self-assured and never concerned that someone less gifted would steal his ideas. Gordan continued, For every problem there were what Albright called ?measuring sticks' - either chemical or bioassay, or the weight of axillary hair, or displacement of water by acromegalic hands and feet, or measurement of height to determine the growth rate, etc. One of his ?Do's' was - do measure something. In his presidential address in 1944, Albright stated that Oliver Wendell Holmes divides intellects into one-story, two-story, and three-story. The latter idealize, imagine, predict; their best illumination comes from above through the skylight. His coworkers and peers appreciated that Albright received illumination through the skylight. Albright also had the capacity to refute accepted dogma and to formulate a working hypothesis of clinical disorders, which he would continuously challenge. Finally, as in the recognition of hormone failure in pseudohypoparathyroidism, Albright understood that when all other possible explanations are eliminated, the remaining explanation no matter how improbable must be true.
Gabe Mirkin MD, who specializes in sports medicine, did an internship at Massachusetts General when Fuller Albright occupied a private room, where he lay in a coma. Mirkin saw Albright at this time and like many physicians held Albright in the highest respect; a role model for all physicians. Mirkin and Fuller Albright's son, Birge Fuller, were in the same class at Harvard. The following was written by Gabe Mirkin MD:
Fuller Albright discovered more new diseases and their causes than any other person in the history of medicine. He was the founder of modern endocrinology, the study of how glands work in your body. In his time, many chairmen of the departments of endocrinology in North American medical schools were men who had studied under him. He was one of the most brilliant and innovative doctors who ever lived. He was also an outstanding athlete who captained his high school football team and was one of the better senior tennis players in New England even though he spent most of his time in his lab at the Mass General Hospital. His life of accomplishment ended with an experimental treatment for Parkinson's disease that left him in a coma for his last thirteen years.
Albright left Harvard after 18 months to enlist in the Army to fight in World War I. During the 1918 pandemic, he was infected with influenza which can cause Parkinson's disease many years later. In 1921, he went to Harvard Medical School and finished at the top of his class. He took his internship and residency at the Massachusetts General Hospital. In 1928, he went to Vienna to study with Dr. Jacob Erdheim. In 1929, Albright returned to the Massachusetts General Hospital and established the world-famous Ward 4, a 10-bed research unit where over the next 15 years, he described many new diseases and was one of the most loved and followed teachers at Harvard Medical School. His students remember this wonderful teacher always dressed in an old tweed jacket, baggy trousers, and a bright-colored bow tie. Married to Claire Birge in 1932, they had two sons. One of his sons, Birge Albright was named after his wife's maiden name, just as his father had named him Fuller after his mother's maiden name. Birge was a classmate of mine (of Gabe Mirkin) at Harvard.
List of Firsts
Try to imagine how one person could make so many breakthroughs in our understanding of how the human body functions. Fuller Albright was the first person to:
- describe the functions of the parathyroid gland,
- associate an overactive parathyroid gland with kidney stones,
- explain the modern diagnosis and treatment of kidney stones,
- develop a method for measuring sex hormones in the urine,
- explain what causes women to have irregular periods or even stop menstruating,
- describe various male sex hormone deficiencies,
- show how certain types of diarrhea cause vitamin deficiencies,
- describe renal tubular acidosis and its treatment,
- show how menopause weakens bones,
- use estrogen to prevent a woman from releasing an egg, setting the stage for the first birth control pills,
- show that progesterone can prevent uterine cancer in women who lack that hormone,
- demonstrate the cause of overactive adrenal glands (Cushing's syndrome),
- warn how dangerous adrenal steroids can be.
- He was the first to describe or characterize the following syndromes, tests and treatments:
Forbes-Albright syndrome (breast milk and absence of periods caused by a brain tumor)
Jaffe-Lichtenstein syndrome (painful, swollen deformity in one bone that fractures easily)
Klinefelter's syndrome (a genetic disorder that causes males to be tall and have small testes with low testosterone, delayed puberty, breast enlargement, reduced facial and body hair, and infertility)
Lightwood-Albright syndrome (acidic blood caused by a kidney defect)
Martin-Albright syndrome (inability to respond to the parathyroid hormone, short stature, short fingers, round face, and mental retardation)
McCune-Albright syndrome (a genetic disease characterized by deformed, easily broken bones, premature sexual maturity, enlargement of the adrenal glands and the overproduction of cortisol)
Morgagni-Turner-Albright syndrome (partial or complete absence of one X-chromosome, ovaries fail to respond to pituitary hormones so they do not produce adequate estrogen, short stature, absence of secondary sexual characteristics, webbing of the neck and inconsistent heart problems)
Ahumada-del Castillo syndrome (women with breast milk not associated with nursing and the absence of menstrual periods due to not releasing an egg each month)
Albright's anemia (anemia in advanced overactive parathyroidism)
Albright's prophecy (in 1945 Albright wrote that preventing ovulation prevents pregnancy and explored the possibility of birth control by hormone therapy)
Albright's syndrome II (Albright hereditary osteodystrophy in which a person has normal levels of parathyroid hormone, but cannot respond to that hormone)
Albright's test (a kidney function test to see how much acid kidneys can clear)
Albright-Butler-Bloomberg disease (a metabolic syndrome marked by dwarfism and other severe developmental anomalies)
Albright-Hadorn syndrome (softening and bending of bones associated with abnormally low concentrations of blood potassium levels)
Chiari-Frommel syndrome (over-production of breast milk and absence of periods for more than six months after giving birth.)
Progression of Parkinson's Disease
In 1937, at age 37, when he was one of the most productive, respected and well known physicians in the world, Albright noticed that his hands started to shake and would become even more shaky when he used them. For example, when he raised a glass of water to his mouth to drink, the shaking would increase as the glass came closer to his mouth. He noticed a progressive slurring of his words as he talked. This former athlete had to walk more slowly because the faster he walked, the more he would lose control of his legs and start to fall. These symptoms progressed very slowly over the next 20 years. He appeared to accept the challenges and did everything he could to overcome his increasing disability. He forced himself to work even harder and discovered many new syndromes and basic mechanisms of how hormones work during this period.
By his early forties, he could not write, and by his mid-forties, he could no longer speak clearly. In his fifties he could not drive a car, so the medical students assigned to him were given the family's second car to drive him to and from the hospital. They also wrote notes for him at work. Many of these students became famous researchers themselves: Howard Rasmussen, James Wyngaarden, Steven Krane, Kurt Isselbacher and Stan Franklin.
Experimental Treatment Disaster
In 1952 Irving Cooper, a New York University neurosurgeon, reported that he could reduce the symptoms of Parkinson's disease by injecting small amounts of alcohol into a part of the brain called the globus pallidus. Because Albright knew that he was losing his ability to reason in addition to losing his ability to eat, dress, write or speak, he went ahead and had the treatment in June 1956. Virtually all of his Harvard colleagues and even Dr. Cooper himself had discouraged him from having the procedure done. After his right side was injected, he noticed less rigidity and better control. He was able to walk comfortably and use his left hand more effectively. He was so encouraged that he had his left side injected, but this procedure resulted in extensive bleeding into his brain. He never recovered and was unable ever to speak again. He spent the next 13 years in a coma, living in a private room at the Massachusetts General Hospital. He was unable to respond to anyone. He died on December 8, 1969.
What is Parkinson's Disease?
When you decide to move a muscle, your brain sends electrical messages between nerves and muscle fibers. When an electrical message reaches the end of a nerve, it releases chemicals called neurotransmitters that travel to the next nerve or muscle fiber to continue the message. Your fine muscle movements are controlled by a neurotransmitter called dopamine that sends messages by passing primarily between two brain areas called the substantia nigra and the corpus striatum.
Most of the movement-related symptoms of Parkinson's disease are caused by a lack of dopamine due to loss of dopamine-producing cells in the substantia nigra. The lower the level of dopamine, the less control you have of your muscles.
We do not know the cause of the loss of dopamine-producing cells. A small percentage of Parkinson patients have other members of their family with the same disease. However, more than 90 percent of people with Parkinson's disease do not have any family history of that disease. Thus most cases of Parkinson's disease appear to be caused by something in the environment, not by a genetic condition.
Risk factors for Parkinson's disease include:
- Toxins: Exposure to manganese, carbon monoxide, cyanide and other chemicals. Some pesticides and herbicides inhibit dopamine production. Farmers are at increased risk for Parkinson's disease.
- Declining estrogen levels: Post-menopausal women and women who have had their ovaries removed are at increased risk.
- Viruses: For example, people who survived exposure to influenza in the 1918 flu pandemic were at increased risk for Parkinson's disease many years later.
- Structural problems: Strokes and fluid buildup in the brain may increase risk of Parkinson's disease.
- Low levels of folic acid: A few studies suggest that folic acid deficiency may cause some cases of Parkinson's disease.
- Head trauma: Any damage to the head, neck, or upper spine increases risk. Boxer Muhammad Ali developed Parkinson's disease very early in life, in his forties.
- Advancing age: Parkinson's disease affects one percent of people over 60 years of age. Risk increases with age.
- Gender: Men are more likely to suffer from Parkinson's than women, possibly because they have greater exposure to other risk factors such as toxins or head trauma.
- Genetic factors: A Mayo-Clinic-led international study revealed that the gene alpha-synuclein may play a role in the likelihood of developing the disease. Studies showed that individuals with a more active gene had a 1.5 times greater risk of developing Parkinson's. These findings support the development of alpha-synuclein suppressing therapies, which may in the long run slow or even halt the disease.