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.”
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In 1995, the field of endocrinology experienced a seismic moment when Jeffrey Friedman, a geneticist at Rockefeller University in New York, found a hormone that no one thought could possibly exist. He named it leptin (from a Greek word for “thin”). Leptin was produced not in an endocrine gland but in fat cells. This was a most arresting discovery. No one had ever suspected that hormones could be produced anywhere but in their own dedicated glands. In fact, we now know, hormones are produced all over the place—in the stomach, lungs, kidneys, pancreas, brain, bones, everywhere.
Leptin drew massive and immediate interest not just because of the surprise of where it was produced but even more because of what it does: it helps to regulate appetite. If we could control leptin, then presumably we could help people to control their weight. In studies with rats, scientists discovered that by manipulating leptin levels, they could make rats obese or lean, as they wished. This had the makings of a wonder drug.
Clinical trials with humans were quickly undertaken, amid considerable anticipation. Volunteers with a weight problem received daily leptin injections for a year. At the end of the year, however, they weighed just as much as they had at the beginning. Leptin’s effects turned out to be nothing like as straightforward as hoped. Today, nearly a quarter of a century after its discovery, we still haven’t figured out exactly how leptin works and are nowhere near being able to use it as an aid for weight control.
A central part of the problem is that our bodies evolved to deal with the challenge of dietary paucity, not overabundance. So leptin isn’t programmed to tell you to stop eating. Nothing chemical in your body is. That’s a big part of why you tend to just keep on consuming. We are habituated into devouring foods greedily whenever we are able on the assumption that abundance is an occasional condition. When leptin is completely absent, you just keep on eating and eating because your body thinks you are starving. But when it is added to the diet, in normal circumstances it makes no discernible difference to appetite. What leptin is there for essentially is to tell the brain whether you have enough energy reserves to undertake comparatively demanding challenges like getting pregnant or starting puberty. If your hormones think you are starving, those processes will not be allowed to begin. That’s why young people who are anorexic often have a very delayed start to puberty. “It’s also almost certainly why puberty starts years earlier now than it did in historic times,” says Wass. “In Henry VIII’s reign, puberty started at sixteen or seventeen. Now it is more commonly eleven. That’s almost certainly because of improved nutrition.”
Complicating matters further is that bodily processes are nearly always influenced by much more than a single hormone. Four years after leptin’s discovery, scientists discovered another hormone involved in appetite regulation. Dubbed ghrelin (the first three letters stand for “growth-hormone related”), it is produced mostly in the stomach but also in several other organs. When we get hungry, our ghrelin levels rise, but it isn’t clear whether ghrelin causes hunger or merely accompanies it. Appetite is also influenced by the thyroid gland and by genetic and cultural considerations and by mood and accessibility (a bowl of peanuts on a table is hard to resist), willpower, time of day, season, and much else. No one has figured out how to pack all that into a pill.