These days, we may be better at the diagnosis and treatment of breast cancer, and the laws of Massachusetts have changed with respect to paired lives, but we are not much further along in neurotic science. From patients humbler than Alice James, we’ve learned that one does not need a “palpable disease” to be in real pain. Patients with psychosomatic diseases are often in anguish, and good doctors address the anguish and not the diagnosis. My own guess is that nowadays Alice James’s illness would have been diagnosed as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, or another one of man’s “medically unexplained diseases.” The British psychiatrist Simon Wessely of King’s College London explains that most medical specialists define unexplained syndromes in the technical terms of their own expertise. Presented with the same cluster of symptoms, what a rheumatologist will call “fibromyalgia” a gastroenterologist would diagnose as “irritable bowel syndrome,” while a neurologist might come up with “chronic fatigue syndrome” and an infectious disease specialist might test for “chronic Lyme disease.” Wessely provides convincing evidence that none of these monikers describes a unique clinical entity; each syndrome shares much with all the others. From epidemiological evidence he concludes that there are strong associations between persistent symptoms such as muscle weakness, stomach cramps, and overall fatigue—the symptoms of Alice’s “rheumatic gout,” one might say. A safer bet, he argues is to describe these conditions honestly as “medically unexplained syndromes.”
Unexplained or not, one more set of medical diagnoses intrudes on the story. A. B. Garrod left us a legacy as imposing as his work in the rheumatic diseases. His son, Sir Archibald Edward Garrod (1857–1936), followed his father’s teachings on the heritable nature of gout. He became interested in a series of rare genetic disorders that, in his Croonian Lectures, he called “inborn errors of metabolism.” And it is thanks to modern studies of inborn errors of metabolism—phenylketonuria is a prime example—that the principle emerged of “one gene, one enzyme.” By means of that principle, Arthur Pardee, François Jacob, and Jacques Monod were able in 1959 to discover how changes in nutrients outside a bacterium can switch single, transmissible genes on or off within a cell: an example of how nurture modifies nature in the dish. This was one of the milestones of molecular biology.
Nowadays, when we treat patients with phenylketonuria by means of an appropriate diet from birth, we can prevent both physical and mental disease, a striking example of how nurture can modify nature in the clinic as well. Clues from the study of depression suggest that the family serpent of gloom in the blood may also turn out to be an inborn error of metabolism. The irony would not have escaped either William or Alice James that the Garrods, who began the science of gout, were present at the birth of “neurotic science.”
A last irony in the story of Alice James is that her legacy is one she could not have imagined. Far better known today than in her lifetime, she has been variously celebrated as a model memoirist, a feminist critic of Victorian mores, a pioneer of narrative medicine, and a lesbian heroine. Over the years, she has become an exemplar in arguments over the role that male physicians play in imposing diseases on women, the role of gender in renown, and the requirement for victimhood in literary honor. Her journal fits into a genre Elaine Showalter has called Hysteries (1998). Cathleen Schine’s first novel, Alice in Bed (1983), is about a woman hospitalized for a medically unexplained disease; the doctors are demons. Susan Sontag’s more recent play, also titled Alice in Bed (1993), is a more fitting tribute; it begins like Gertrude Stein and ends in a benediction. The play opens with the voice of Alice’s nurse in Leamington:
NURSE:
Of course you can get up
ALICE:
I can’t
NURSE:
Won’t
ALICE:
Can’t
NURSE:
Won’t
Later Alice soliloquizes about Rome, a city that she, unlike her famous brothers, has never seen: “I would be very humble. Who am I, compared with Rome. I come to see Rome, it doesn’t come to see me. It can’t move.” The play ends with Alice saying, “Let me fall asleep. Let me wake up. Let me fall asleep.” To which her nurse replies, “You will.”
She wakes up on every page of her journal.
15.
Free Radicals Can Kill You: Lavoisier and the Oxygen Revolution
MME LAVOISIER: Imagine what it means to understand what gives a leaf its color! What makes a flame burn. Imagine!
—Carl Djerassi and Roald Hoffmann, Oxygen (2001)
Oxygen is nothing other than the most salubrious and purest portion of the air, such that . . . it appears in an eminently respirable state more capable than the air of the atmosphere of sustaining ignition and combustion.
—Antoine-Laurent Lavoisier (1775)
. . . though pure dephlogisticated air [oxygen] might be useful as a medicine, it might not be so proper for us in the usually healthy state of the body; for as a candle burns out much faster in dephlogisticated than in common air, so we might, as may be said, live out too fast, and the animal powers be too soon exhausted in this pure kind of air. A moralist, at least, may say, that the air which nature has provided for us is as good as we deserve.
—Joseph Priestley (1775)
. . . there are good reasons for assuming that the changes produced by irradiation and those which arise spontaneously in the living cell have a common source—the OH and HO2 radicals.
—Denham Harman (1956)
I’M GETTING WORRIED ABOUT OXYGEN: not having too little of it, but too much. We’ve known since Lavoisier that flames burn, metals rust, and we take breath—all thanks to oxygen. But we hadn’t learned how oxygen excess does harm until 1954, when Rebecca Gerschman et al. worked out that oxygen poisoning and x-irradiation share the property of producing oxygen-derived free radicals. Add one electron to oxygen, as by irradiation, and superoxide anion (O2–•) is formed; that’s a free radical anion. Add two electrons, and you get a bleach, hydrogen peroxide (H2O2), which is not a free radical but can readily react with O2–• to form the very reactive hydroxyl radical (OH•). Add any of these to living tissues, and they do damage. On the basis of this chemistry, Denham Harman formulated his heuristic “free radical theory of aging”:
. . . In regard to aging, I felt that there had to be a basic cause which killed everything. Further, this basic cause should be subject to genetic and environmental influences.
It is no accident that Gerschman’s and Harman’s laboratories were funded by the Atomic Energy Commission. As Harman later observed, the work “was of particular interest in 1954 because of concern over possible nuclear war.” Well, thanks to the Cold War and the last fifty-odd years of research in the area, we’ve learned that Priestley was right about that burning candle. We’ve learned that we do “live out too fast,” and our animal powers are indeed “too soon exhausted” when we are bombarded by oxygen-derived free radicals, whether generated from without or within our own bodies.
The flood of publications dealing with oxidative stress has risen dramatically in recent years. Scanning papers with “oxidative stress” in the title, I checked out the website Web of Science. Sure enough, between 2005 and mid 2017, papers dealing with oxidative stress had increased 300-fold. In 2005, papers dealing with low oxygen (hypoxia) exceeded in popularity the hyperoxic condition, but by mid-2017, articles on oxidative stress (279,243) were beating hypoxia (122,644) by more than 2:1. Priestly would have been pleased.
MANY OF THOSE PAPERS SPELL OUT THE FACT that we age by the same mechanism by which metals rust, photos fade, and wicker frays. They also confirm Harman’s prediction that in our bodies, these processes are “subject to genetic and environmental influences.” We know that genetic defects in one or another of our own defenses against those free radicals, such as superoxide dismutase or ceruloplasmin, cause serious disease. Our cells also make reactive oxygen species, not only in the course of mitochondrial respiration within cells
, as already surmised by Gerschman et al. Our inflammatory cells also assemble machinery for making 02–• and OH• on the cell surface. In concert with a newly recognized brew of reactants formed from NO, ozone, and so on, these wreak havoc with our cells and extracellular constituents. Lavoisier had the chemistry right when he told us what happened to the animal “oils” of our cells when oxygen reacts:
It is evident that the oils, being composed of hydrogen and charcoal combined, are true carbono-hydrous or hydro-carbonous radicals; and, indeed by adding oxygen, they are convertible to vegetable oxides and acids according to their degrees of oxidation.
And that was before hydroperoxy and peroxy fatty acids—our time’s version of vegetable oxides—were on our screens.
ANTOINE-LAURENT LAVOISIER AND HIS WIFE, Marie-Anne, are depicted in the most beautiful image of scientific coworkers ever put on canvas. Jacques-Louis David’s 1788 portrait of this unusual couple is not only an image of Enlightenment grace and grandeur but also a document of a work in progress for which both of the principals are responsible—the revolutionary Traité élémentaire de chimie of 1789. It justifies the later appellations of Lavoisier as the father and Mme Lavoisier the mother of modern chemistry.
Lavoisier is shown with quill on paper, looking up at his wife as if to take dictation or suggestion. The instruments on the table and floor are those used by Lavoisier to give “the first accurate accounts of burning, respiration and rusting.” Mme Lavoisier is depicted with her arm on her husband’s shoulder, and the stand behind her could well contain drawings for some of the thirteen plates she fashioned for the Traité de chimie. Lavoisier’s mid-script attention to his wife reminds me of her important translation of Richard Kirwan’s treatise on the presumed substance “phlogiston”. Her modest smile directed at the viewer—and the portraitist—suggests a strong student–teacher bond. Marie-Anne was an apt pupil of David: her skillful student drawings, with David’s comments, are in the Musée des Arts et Métiers in Paris today.
The painting also documents a concurrence of three revolutions: the American, the French, and the Chemical. It is set in the Arsenal of Paris, to which Lavoisier had been appointed as commissioner of the Royal Gunpowder and Saltpeter Administration. His charge, so to speak, was to greatly improve the purity and efficacy of French explosives. He fulfilled this task admirably: in aid of his American friends, Thomas Jefferson and Benjamin Franklin, he guaranteed the colonists a trusty supply of neat gunpowder to fight the redcoats. Indeed, Franklin was a good friend of both Lavoisiers. Recovering from an attack of gout in Philadelphia, Franklin wrote to Marie-Anne in 1783 to thank her for a portrait she had painted of him for its “great merit as a picture in every respect; but what particularly endears it to me, is the hand who drew it.” He was only one of Marie-Anne’s many admirers, who included Gouverneur Morris, Pierre Samuel du Pont de Nemours, and Benjamin Thompson, Count Rumford. As Roald Hoffmann lamented, “There is no biography of Mme Lavosier. I think she deserves an opera.”
DISPUTE HAS RAGED OVER WHICH OF THE THREE CHEMISTS who came across oxygen between 1772 and 1778 deserves credit for the air of life. It is now agreed that a Swede discovered it first, the “fire air” of Carl Wilhelm Scheele in 1772; a Briton published it first, the “dephlogisticated air” of Joseph Priestley in 1775; and a Frenchman understood it first, the “oxygen” of Lavoisier in 1775–1778. J. W. Severinghous suggests that Lavoisier may have heard about Scheele’s and/or Priestley’s work directly or indirectly. But there’s surely credit enough for all three to split the “retro-Nobel” awarded by Carl Djerassi and Roald Hoffmann in their sparkling play, Oxygen
At the Arsenal, Lavoisier extended his work on “oxygen” (he gave it the name from the Greek for “acid-forming”) as the mediator of fire and life. He also proposed the first systematic enumeration of elements, a precursor of Mendeleev’s periodic table:
Thus, while I thought myself employed only in forming a Nomenclature, and while I proposed to myself nothing more than to improve the chemical language, my work transformed itself by degrees, without my being able to prevent it, into a treatise upon the Elements of Chemistry.
The treatise helped him to formulate the law of the conservation of matter: nothing is lost in a chemical reaction. In perhaps his most vital work, he showed that living beings transform oxygen in the course of respiration, that they consume energy and generate heat, and that muscular exercise burns calories as a candle does. One can measure this process. He called it calorimetry.
Alas, Lavoisier fell to the guillotine, not for his science but for his business interests. Lavoisier was one of approximately two dozen partners—among them, Mme Lavoisier’s father—in a private, for-profit corporation, the Ferme générale. The Ferme functioned as a crop-inspection and tax-collecting agency working on behalf of the crown. The proceeds from Lavoisier’s share of Ferme générale revenue are said to have paid for his experiments at the Arsenal.
After July 14, 1789, Lavoisier became a staunch supporter of the liberal constitutional monarchy set up in response to the fall of the Bastille. In the upbeat interregnum of 1790, he wrote to Benjamin Franklin of the two revolutions that were still in progress. Lavoisier, supported by his colleagues at the Academy of Sciences, had overthrown the reigning “phlogiston” theory. Phlogiston had been tautologically defined as a “fire-like” element in any substance undergoing combustion, but Lavoisier showed that the fire-enabling substance could come from air: oxygen. Lavoisier exulted to Franklin: “Here then a revolution has taken place in an important part of human knowledge since your departure from Europe.” He was equally happy with the change in French political life: “After having brought you up to date on what is going on in chemistry, it would be well to speak to you about our political revolution. We regard it as done and without possibility of return to the old order.”
THE OLD ORDER DIDN’T RETURN, but the Reign of Terror descended, and the tumbrels rolled. By 1792, the radical Jacobins were calling for heads, not only of the body politic. In quieter times, Jean-Paul Marat, that self-proclaimed genius of “optics, soap bubbles and medical electricity,” had been denied admission repeatedly to the Academy of Sciences. Unleashed by the Terror, he called for abolition of all of the academies. In his broadsheet, L’ami du peuple, he attacked Lavoisier personally:
I denounce . . . the leader of the chorus of charlatans, Sieur Lavoisier, son of a land-grabber, apprentice-chemist, pupil of the Genevan stock-jobber [Jacques Necker, Louis XVI’s finance minister], a Fermier-géneral, Commissioner for Gunpowder and Saltpeter, Governor of the Discount Bank, Secretary to the King, Member of the Academy of Sciences.
Together with the constitutional monarchy, the Ferme générale was swept aside in the course of the Revolution. The radical Jacobins moved from mass protest to mass murder in what came to be called the “September massacres” of 1792. Lavoisier’s laboratory at the Arsenal was shut forever, and the Academy of Sciences dissolved shortly thereafter. In November 1793, Lavoisier, his father-in-law, and twenty-six others of the Ferme générale were imprisoned and accused of “having plundered the people and the treasury of France, and of having adulterated the nation’s tobacco with water, etc.” All were found guilty after a one-day trial and condemned to the guillotine on May 8, 1794.
Two apocryphal quotations survive from the trial. One is attributed to Jean-Baptiste Coffinhal du Bail, the judge who dismissed appeals that cited Lavoisier’s scholarly contributions to chemistry and the nation: “La République n’a pas besoin de savants ni de chimistes! (The Republic needs neither scholars nor chemists!)” The other, attributed to the mathematician Joseph-Louis Lagrange, may be more authentic:
It took them only a moment to sever that head, and a hundred years perhaps will not suffice to produce another like it.
Close enough: Albert Einstein was born in 1879.
16.
Dr. Blackwell Returns from London
You ask, what use will she make of her liberty when she has so long been
sustained and restrained? I answer in the first place this will not be suddenly given. . . . But were this freedom to come suddenly, I have no fear of the consequences. . . . If you ask me what offices they may fill, I reply—any. I do not care what case you put; let them be sea captains if they will. I do not doubt there are women fitted for such an office. . . .
—Margaret Fuller, Woman in the Nineteenth Century (1845)
MARGARET FULLER AND HER HUSBAND AND INFANT SON were drowned by shipwreck on July 19, 1850, when an inexperienced sea captain ran aground the ship in which they were traveling on a sandbar off Fire Island, New York. Exactly one year later, another American woman returned to America from postgraduate medical studies in London to a reception only somewhat more hospitable than Fuller’s. Dr. Elizabeth Blackwell (1821–1910), described by the Lancet as “the first woman medical graduate in the modern meaning of the phrase,” arrived in New York to set up medical practice. She, too, followed her medical vocation at the École de Médecine, where Dr. Holmes had studied, while her life in reform realized George Eliot’s hope that the profession would combine the goals of intellectual conquest with social good. In several aspects Dr. Blackwell’s career paralleled that of Dr. Holmes. Children of preachers, both had imbibed the sternest of Puritan values, both softened their views in the light of French culture, both lived in the service of public hygiene. Both strongly opposed the heresies of Mesmer and homeopathy, and both strongly believed that meliorist reason would “increase the power of positive good” in the new republic.
Born in England to Samuel Blackwell, a well-off sugar refiner and dissident lay preacher, Elizabeth and her eight siblings were brought to live in Cincinnati, where family friends soon included Henry Ward Beecher and Harriet Beecher Stowe. Her exposure to Unitarian thought in Cincinnati and to Quaker physicians in Philadelphia turned her interests to medicine, and she received medical tutorials in the private practices of friendly doctors. Despite thorough preparation in anatomy classes and a solid educational record, she was refused admission by every medical faculty in Philadelphia, New York City, and Boston, and by Bowdoin and Yale.
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