The Body, page 16
At the time I met him, he believed they were three years away from trials in humans, and perhaps ten years from using it clinically.
In the meantime, it remains a slightly humbling reflection that about a million times per second our bodies do something that all the science of the world put together so far cannot do at all.
*1 Barnard’s was the first human-to-human heart transplant. The first heart transplant of any type involving a human was in January 1964, when a Dr. James D. Hardy in Jackson, Mississippi, transplanted a chimpanzee’s heart into a man named Boyd Rush. The patient died within an hour. Morris, Heart of the Matter, 225.
*2 The term “stent” has a curious history. It is named after Charles Thomas Stent, a nineteenth-century London dentist who had nothing to do with heart surgery. Stent was the inventor of a compound used to make dental molds, which oral surgeons eventually also found useful when doing repairs to the mouths of soldiers wounded in the Boer War. Over time, the term came to be used for any kind of device used to keep tissue in place during corrective surgery and, in the absence of a better term, gradually took up a position as the word of choice for an arterial support for cardiac surgery. The record for stent insertions, incidentally, appears to be held by a fifty-six-year-old man in New York who, at last report, had had sixty-seven stents inserted for angina in a period of ten years. according to the Baylor University Medical Center Proceedings. Charles Stent profile, Journal of the History of Dentistry, July 2001; Baylor University Medical Center Proceedings, April 2011, 158.
*3 If our blood is red, incidentally, why do our veins look blue? It is simply a quirk of optics. When light lands on our skin, a higher proportion of the red spectrum is absorbed, but more of the blue light is bounced back, so blue is what we see. Color is not some innate feature that radiates out of an object but rather a marker of the light bouncing off it.
*4 Rh factor is the name for a kind of surface protein called an antigen. People who have the Rh antigen (about 84 percent of us) are said to be Rh-positive. Those who lack it, the remaining 16 percent, are Rh-negative.
8 THE CHEMISTRY DEPARTMENT
I hope my disease of the stone may not return to me, but void itself in pissing, which God grant, but I will consult my physitian.
—SAMUEL PEPYS
I
DIABETES IS A horrible disease, but once it was even worse because people could do almost nothing about it. Youngsters with diabetes generally died within a year of diagnosis, and it was a miserable death. The only way to reduce sugar levels in the body, and extend lives even slightly, was to keep victims right on the edge of starvation. One twelve-year-old boy was left so hungry that he was caught eating birdseed from the tray of a canary cage. Eventually he died, as all victims died, famished and wretched. He weighed thirty-nine pounds.
Then, in late 1920, in one of the happiest but most improbable episodes in the history of scientific progress, a struggling young general practitioner in London, Ontario, read an article about the pancreas in a medical journal and got an idea for how he might effect a cure. His name was Frederick Banting, and he knew so little about diabetes that he misspelled it as “diabetus” in his notes. He had no experience of medical research, but he was convinced that he had a notion worth pursuing.
The challenge for anyone tackling diabetes was that the human pancreas has two quite separate functions. Most of it is devoted to making and secreting enzymes that assist in digestion, but the pancreas also contains clusters of cells known as islets of Langerhans. These were discovered in 1868 by a medical student in Berlin, Paul Langerhans, who freely admitted that he had no idea what they were there for. Their function, to produce a chemical that was at first called isletin, was deduced twenty years later by a Frenchman, Édouard Laguesse. We now call that chemical insulin.
Insulin is a small protein that is vital in maintaining a very delicate balance of blood sugar in the body. Too much or too little produces terrible consequences. We get through a lot of insulin. Each molecule only lasts from five to fifteen minutes, so the demand for replenishment is relentless.
The role of insulin in controlling diabetes was well known by Banting’s time, but the problem was separating it from the digestive juices. Banting’s belief—based on no evidence whatever—was that if you tied off the pancreatic duct and stopped digestive juices from getting to the intestines, the pancreas would stop producing them. There was no reason at all to suppose that this would happen, but he persuaded a professor at the University of Toronto, J. J. R. Macleod, to let him have some lab space, an assistant, and some dogs on which to experiment.
The assistant was a Canadian American named Charles Herbert Best who had grown up in Maine, where his father was a small-town general practitioner. Best was conscientious and willing but, like Banting, knew almost nothing about diabetes and even less about experimental methods. Nonetheless, they set to work, tying off pancreatic ducts in dogs, and, amazingly, got good results. They did almost everything wrong. As one observer put it, their experiments were “wrongly conceived, wrongly conducted, and wrongly interpreted.” Yet within weeks they were producing pure insulin.
When given to diabetics, the effect was nothing short of miraculous. Listless, skeletal patients who could barely be called alive were swiftly restored to full vibrancy. It was, to borrow from Michael Bliss, author of the definitive The Discovery of Insulin, the closest thing to resurrection modern medicine had ever produced. Another researcher in the lab, J. B. Collip, came up with a more effective method for extracting insulin, and soon it was being produced in vast enough quantities to save lives all over the world. “The discovery of insulin,” declared the Nobel laureate Peter Medawar, “may be rated the first great triumph of medical science.”
It should have been a happy story for all concerned. In 1923, Banting was awarded the Nobel Prize in Physiology or Medicine along with Macleod, the head of the lab. Banting was appalled. Not only had Macleod not been involved in the experimental work, he hadn’t even been in the country when the breakthrough was made, but rather was on an extended annual visit to his native Scotland. Banting clearly thought Macleod did not deserve the honor and announced that he would share the prize money with his trusty assistant Best. Collip, meanwhile, refused to share his improved extraction method with the rest of the team and announced that he intended to patent the procedure in his own name, infuriating the others. Banting, who seems to have had a short fuse in life anyway, on at least one occasion had to be pulled off Collip after physically attacking him.
Best for his part couldn’t stand Collip or Macleod and eventually ended up disliking Banting, too. In short, they more or less all ended up loathing one another. But at least the world got insulin.
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Diabetes comes in two varieties. Indeed, it is really two diseases, with similar complications and management issues but generally different pathologies. In type 1 diabetes, the body stops producing insulin altogether. In type 2 diabetes, insulin is less effective, usually because of a combination of decreased production and because the cells on which it acts don’t respond as they normally would. This is referred to as insulin resistance. Type 1 tends to be inherited; type 2 is usually a consequence of lifestyle. But it’s not quite as simple as that. Although type 2 is unequivocally associated with unhealthy living, it also tends to run in families, suggesting a genetic component. Similarly, although type 1 diabetes is associated with a fault in a person’s HLA (human leukocyte antigen) genes, only some people with the fault get diabetes, indicating that there is some additional, unrecognized trigger. Many researchers suspect a link to levels of exposure to a range of pathogens in early life. Others have suggested an imbalance in the victim’s gut microbes or possibly even a connection to how comfortable and well nourished one was in the womb.
What can be said is that rates everywhere are soaring. Between 1980 and 2014, the number of adults in the world with diabetes of one type or another went from just over 100 million to well over 400 million. Ninety percent of them had type 2 diabetes. Type 2 is growing especially fast in developing countries that have been adopting our bad Western habits of poor diet and inactive lifestyle. Yet type 1 is also growing swiftly. In Finland, it has gone up by 550 percent since 1950. It continues to rise almost everywhere at a rate of about 3 to 5 percent a year, for reasons no one understands.
Although insulin has transformed the lives of millions of diabetics, it is not a perfect solution. For one thing, it cannot be given orally, because it is broken down in the gut before it can be absorbed and put to use, so it must be injected, which is both a tedious process and a crude one. In a healthy body, insulin levels are monitored and adjusted second by second. In a diabetic, they are adjusted only periodically, when the patient self-medicates. That means that insulin levels are still not quite right much of the time, and that has a cumulative negative effect.
Insulin is a hormone. Hormones are the bicycle couriers of the body, delivering chemical messages all around the teeming metropolis that is you. They are defined as any substance that is produced in one part of the body and causes an action somewhere else, but beyond that they are not easy to characterize. They come in different sizes, have different chemistries, go to different places, have different effects when they get there. Some are proteins, some are steroids, some are from a group called amines. They are linked by their purpose, not their chemistry. Our understanding of them is far from complete, and much of what we do know is surprisingly recent.
John Wass, professor of endocrinology at Oxford University, is smitten with hormones. “I love hormones,” he likes to say. When we met, in a café in Oxford at the end of a long working day, he was clutching an armful of disorderly papers but looking surprisingly fresh for someone who had flown in that morning from ENDO 2018, the annual conference of the Endocrine Society in the United States.
“It’s madness,” he tells me in a delighted tone. “You have eight or ten thousand endocrinologists from all over the planet. The meetings start at five thirty in the morning and can go on until nine o’clock at night, so there’s a lot to take in and you end up with”—he shakes the papers for me—“a lot of reading. It’s very useful but a bit mad.”
Wass is a tireless campaigner for a better appreciation of hormones and what they do for us. “They were the last major system in the body to be discovered,” he says. “And we are still discovering more all the time. I know I am biased, but it is really a terribly exciting field.”
As late as 1958, only about twenty hormones were known. No one seems to know quite how many there are now. “Oh, I think it must be at least eighty,” says Wass, “but perhaps as many as a hundred now. We really do keep discovering more all the time.”
Until very recently, it was thought that hormones are produced exclusively in the body’s endocrine glands (hence the name endocrinology for this branch of medicine). An endocrine gland is one that secretes its products directly into the bloodstream, as opposed to exocrine glands, which secrete onto a surface (like sweat glands onto skin or salivary glands into the mouth). The principal endocrine glands—the thyroid, parathyroid, pituitary, pineal, hypothalamus, thymus, testes (in men), ovaries (in women), pancreas—are scattered all around the body but work together closely. They are mostly tiny and altogether weigh no more than a few ounces but have an importance to your happiness and well-being that is entirely disproportionate to their modest dimensions.
The pituitary gland, for instance, which is buried deep within your brain directly behind your eyes, is only about the size of a baked bean, yet its effects can be—literally—enormous. Robert Wadlow of Alton, Illinois, the tallest human who ever lived to that point, had a pituitary condition that caused him to grow ceaselessly because of continuous overproduction of growth hormone. A shy and cheerful soul, he was taller than his (normal-sized) father by the age of eight, was 6 feet 11 inches tall at the age of twelve, and over 8 feet tall when he graduated from high school in 1936—all because of a little chemical overexertion by this baked bean in the middle of his skull. He never stopped growing and was just a fraction under 9 feet tall at his greatest eminence. Though not fat, he weighed about five hundred pounds. His shoes were a size 40. By his early twenties, he could walk only with great difficulty. To support himself, he wore leg braces, which caused chafing, and that led to a serious infection that grew septic and killed him as he slept on July 15, 1940. He was just twenty-two. His height at death was 8 feet 11.1 inches. He was much loved and is still celebrated in his hometown.
It is clearly ironic that such a large body resulted from a malfunction in a minuscule gland. The pituitary is often called the master gland because it controls so much. It produces (or regulates the production of) growth hormone, cortisol, estrogen and testosterone, oxytocin, adrenaline, and much else. When you exercise vigorously, the pituitary squirts endorphins into your bloodstream. Endorphins are the same chemicals released when you eat or have sex. They are closely related to opiates. That’s why it is called the runner’s high. There is barely a corner of your life that the pituitary doesn’t touch, yet its functions weren’t even broadly understood until well into the twentieth century.
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The field of modern endocrinology got off to a somewhat bumpy start, in good measure because of the enthusiastic but misguided endeavors of an otherwise brilliant man named Charles-Édouard Brown-Séquard (1817–94). Brown-Séquard was a man literally of many nations. He was born on the Indian Ocean island of Mauritius, which made him Mauritian and British because Mauritius was then a British colony, but his mother was French and his father was American, so he had claims to four nationalities from the moment of his first breath. He never met his father, a ship’s captain who was lost at sea before his son’s birth. Brown-Séquard grew up in France and trained as a physician there but then rotated between Europe and America, seldom staying in either long. In one twenty-five-year period, he made sixty Atlantic crossings—this when one trip in a lifetime was exceptional—taking up a variety of posts, many of considerable eminence, in Britain, France, Switzerland, and the United States. During the same period, he wrote nine books and more than five hundred papers; edited three journals; taught at Harvard, the University of Geneva, and the Faculté de Médecine in Paris; lectured widely; and became a leading authority on epilepsy, neurology, rigor mortis, and the secretions of glands. But it was an experiment he conducted in Paris in 1889, at the stately age of seventy-two, that secured his permanent, and somewhat risible, fame.
Brown-Séquard ground up the testes of domesticated animals (dogs and pigs are most often cited, but no two sources seem to quite agree on which animals he favored), injected the extract into himself, and reported feeling as frisky as a forty-year-old. In fact, any improvement he sensed was entirely psychological. Mammalian testes contain almost no testosterone because it is sent out into the body as quickly as it is made, and in any case we manufacture very little of it anyway. If Brown-Séquard ingested any testosterone at all, it was no more than a trace. Even though Brown-Séquard was completely wrong about the rejuvenative effects of testosterone, he was actually right that it is potent stuff—so much so that, when synthesized, it is treated today as a controlled substance.
Brown-Séquard’s enthusiasm for testosterone seriously damaged his scientific credibility, and he died soon afterward anyway, but ironically his efforts prompted others to look more closely and systematically at the chemical processes that control our lives. In 1905, a decade after Brown-Séquard’s death, the British physiologist E. H. Starling coined the term “hormone” (on advice from a classics scholar at Cambridge University; it comes from a Greek word meaning “to set in motion”), though the science didn’t really get going until the following decade. The first journal devoted to endocrinology wasn’t founded until 1917, and the umbrella term for the ductless glands of the body, the endocrine system, came even later. It was coined in 1927 by the British scientist J. B. S. Haldane.
Arguably the real father of endocrinology lived a generation before Brown-Séquard. Thomas Addison (1793–1860) was one of a trio of outstanding doctors, known as the Three Greats, at Guy’s Hospital in London in the 1830s. The others were Richard Bright, discoverer of Bright’s disease (now called nephritis), and Thomas Hodgkin, who specialized in disorders of the lymphatic system and whose name is commemorated in Hodgkin’s and non-Hodgkin’s lymphomas. Addison was probably the most brilliant, certainly the most productive, of the three. He provided the first accurate account of appendicitis and was a leading authority on all types of anemia. At least five serious medical conditions were named for him, of which the most famous was (and remains) Addison’s disease, a degenerative disorder of the adrenal glands that Addison described in 1855, making it the first hormonal disorder to be identified. Despite his fame, Addison was subject to spells of depression, and in 1860, five years after identifying Addison’s, he retired to Brighton and killed himself.
Addison’s disease is a rare but still-serious illness. It affects about one person in ten thousand. History’s most famous sufferer was John F. Kennedy, who was diagnosed with it in 1947, though he and his family always emphatically and untruthfully denied it. In fact, Kennedy not only had Addison’s but was lucky to survive it. In those days, before the introduction of glucocorticoids, a type of steroid, 80 percent of sufferers died within a year of diagnosis.
John Wass, at the time we met, was particularly preoccupied with Addison’s disease. “It can be a very sad disease because the symptoms—principally loss of appetite and weight loss—are easily misdiagnosed,” he told me. “I recently dealt with the case of a really lovely young woman, just twenty-three years old and with a very promising future in front of her, who died of Addison’s because her doctor thought she was suffering from anorexia and sent her to a psychiatrist. Addison’s in fact arises from an imbalance of cortisol levels—cortisol being a stress hormone that regulates blood pressure. The tragedy of it is that if you correct the cortisol problem, the patient can return to normal health in as little as thirty minutes. She needn’t have died at all. A big part of what I do is lecture to general practitioners to try to help them to look out for common hormonal disorders. They are all too often missed.”
