‘Autopsies of Many Kinds’

One hundred and fifty years ago, the magazine Popular Science launched its first issue, edited by the optimistic polymath Edward Youmans. Youmans, who published and lectured for general audiences on subjects ranging from the laws of thermodynamics to “The Science of Prohibition” and “The Culture Demanded by Modern Life,” admonished readers that “whoever desires to be intelligent as to contemporary movements in the world of thought…must give attention to the course of scientific inquiry.”

By “science” Youmans meant both a limitless, grandly ecumenical way of being in the world—anyone applying “continuous intelligent observation” to biology, chemistry, political theory, or “the characters of men” was producing science—and something quite specific, namely an Anglo-American Victorian combination of nascent evolutionary biology with strong Transcendentalist and liberal Protestant undertones. Whereas Scientific American, founded in 1845, focused on applied science’s gadgetry and news from the US Patents Office, Popular Science offered middle-class nonprofessionals distillations of Darwin, Huxley, Spencer, Lyell, and others. With those missives from the scientific vanguard, subscribers were tacitly promised at least passive participation in mankind’s quasi-divine march toward a more humane, rational, successful, and peacefully organized future.

Readers could also be reassured that while the latest from natural selection theory, plate tectonics, or paleontology might seem like dramatic upheavals of the known world, these would drape gently over old schema, showing merely novel aspects of “the infinite wisdom of the Creator,” as Youmans put it elsewhere. The new wine would taste exciting. And the old bottles in which it was decanted would still be revered.

The mid-nineteenth-century mania for popularized science—sometimes dubbed “expository science” by historians, to emphasize that audiences for its wide-circulation periodicals, traveling lecturers and demonstrations, and loosely scientific social clubs might well be a mix of casual armchair perusers and true career professionals—ebbed somewhat toward the end of the nineteenth century. Professional societies in various disciplines began circling the wagons and pushing for new forms of credentialization, often improving standards in education and research while making science more exclusionary. (In American health care, for example, the relatively new idea of cross-institutional standards that enabled medical schools to grant accredited degrees led to the closure of all but two of the schools willing to enroll Black students, and all but one of the medical schools for female students.) The ordinary person’s curiosity about scientific developments was partially sublimated into science fiction and entertainment, and later a cultural preoccupation with war technology and other dark fusions of applied science and the national interest.

We have perhaps just experienced another spring tide in the cyclical appetite of the general public to know what scientists are up to. At the height of the Covid-19 pandemic it felt as though everyone with an Internet connection ought to be able to explain how an mRNA vaccine works—even, and perhaps especially, antivaxxers, who often cited abstruse and poorly conducted but professional-looking studies about things like the protein composition of the human placenta. Central to the usual litany of liberal credos over the past few years has been the idea that “Science Is Real.” (Prior to Covid-19 this usually referred to climate change research, though by 2020 “science” tended to mean a more open-ended “public health consensus.”) And throughout the late twentieth and early twenty-first centuries, media roundups of the year in events—Time magazine’s Person of the Year, for example—have as often chosen a breakthrough in science and technology as a political or cultural figure when trying to convey that we live in unprecedented times.

Some of the success of the oncologist Siddhartha Mukherjee’s best-selling and Pulitzer Prize–winning books derives from his ability to combine many kinds of science writing at once, blending biography, the history of ideas, mechanistic explanations of biology and chemistry, and reports from the vanguard of nascent theory. His books narrate the history and the predicted future of medicine through anecdotes about the powerful and the powerless, while distilling the major hypotheses of the field into graspable stories and metaphors. These tales are occasionally interspersed with instruction on how readers might better conceive of their own health or think more like a doctor or scientist. His choice of subjects has also tended to anticipate public curiosity—about cancer (The Emperor of All Maladies, 2010), genetics (The Gene: An Intimate History, 2016), and now cell biology.

Mukherjee’s prose often has a quiet loveliness, produced by the tension between his instinct for lush description and his respect for accuracy. His introduction to The Song of the Cell describes the relation between cells and genes in the typical summary fashion of any biology primer, but then adds a characteristic fillip, both charming and true: “A cell enlivens genes.” Moreover, “the life of an organism reposes in the life of a cell.” The compression and aptness of those verbs take us far beyond the jargon of the textbook.

Mukherjee walks us through the earliest scientific discovery, that all living things originate from proliferations of cells and that disease arises when either our own cells cease their smooth functioning or else invading entities—often single-celled organisms—damage our cellular structures from within. The story begins with the gifted Dutch amateur Antonie van Leeuwenhoek and the British polymath Robert Hooke, who experimented with rudimentary microscopes in the late seventeenth century. Both were intrigued by the wriggling cacophony of tiny organisms, magnified perhaps up to fifty times larger by Hooke, and an astonishing two hundred to three hundred times larger by Leeuwenhoek. Hooke also made the less glamorous but equally groundbreaking discovery of “a great many little boxes” forming the latticework of plants and animals: cells bound together into tissue.

Hooke’s inability to understand the significance of these tiny bound chambers, combined with his irascible temper (he picked unwinnable fights with Isaac Newton), nearly guaranteed the dormancy of cell biology until the early nineteenth century, when the zoologist Theodor Schwann and the botanist Matthias Schleiden recognized that though the organisms each of them specialized in “present different modifications, [they] are yet essentially the same.” By the mid-nineteenth century Rudolf Virchow’s conviction that “cellular pathology” explained disease, along with Robert Koch’s, Ignaz Semmelweis’s, and John Snow’s early forays into germ theory and epidemiology, began to link microcosm to macrocosm. Each tiny world within a cell mirrored the alternating periods of health or affliction visible in individuals, households, cities, and nations.

Though Mukherjee renders these men in vigorous strokes of portraiture, he is also careful to note that the march of science is not merely a relay race of geniuses. Big thinking is not enough: trails of discovery go cold if the humbler work of artisans, technicians, and bureaucrats has not yet produced sufficient quantity or quality of glass lenses, public records, autoclaves, catheters, or any number of other instruments without which much of cell biology would be mere idle speculation.

Good ideas may also fall on deaf ears if misunderstood as mere cultural symptoms. Take the case of the evolutionary biologist Lynn Margulis, who in 1967 proposed that mitochondria (tiny energy factories inside the cell) had once been independent organisms, “engulfed” by more complex organisms in an ancient case of symbiosis. At the time, her vision of an “orgy of cooperation” between mitochondria and their host cells seemed an excess of 1960s countercultural sensibility, all too closely mirroring a social landscape in which “young men and women [were] engulfing each other with ardor,” as Mukherjee puts it. Her theory was largely dismissed until the rise of DNA sequencing in the 1980s began to verify it.

At other times, world-historical leaps in understanding can seem to outpace and transcend any one scientist’s or lab’s deductive labor: as Mukherjee writes in The Emperor of All Maladies, sometimes “an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself.” Or else the puzzle pieces may be set in place by human hands, though too many and too ancient to name. The history of vaccination, for example,

is one of veiled hearsay, gossip, and myth. Its heroes are nameless: the Chinese doctors who air-dried the first pox pustules; the mysterious sect of worshippers of Shitala who ground viral matter with boiled rice and inoculated it into children; the Sudanese healers who came to discern the ripest lesions.

As The Song of the Cell moves into the twentieth and twenty-first centuries, Mukherjee not only recounts the history of our understanding of embryology, blood types, organ transplantation, the formation of the immune system, the synaptic communication of neurons, and the like, but also pauses to summarize—with occasional diagrams—the biological mechanisms underpinning each.

One fascinating section explains how our evolving understanding of cell division is aiding in vitro fertilization. Since the early 1980s, when the cell biologist (and later Nobel winner) Tim Hunt began studying how sea urchin eggs are fertilized, scientists have noted that certain proteins and the enzymes that activate them determine when, and whether, cells divide their genetic material to make new cells. As guardians of healthy cell division, these proteins and enzymes (now known as cyclins and cyclin-dependent kinases (CDK), respectively) control the process so that only genetically viable cells continue dividing and maturing. If cyclin-CDK regulation is too permissive, abnormal cells and tissue are made; if too strict, division doesn’t go forward. These cyclin-CDK “checkpoints” have such elegant and replicable choreography that biologists can essentially—at least in research settings—monitor a cell with a stopwatch in order to discern whether cell division is self-regulating in ways that will result in genetically healthy daughter cells.

A “perpetual frustration of medically assisted reproduction,” Mukherjee writes, is that not all chromosomally normal, healthy-appearing embryos will grow to become viable fetuses. Ever since the advent of IVF, one common response to this conundrum has been to transfer more than one embryo simultaneously into the uterus. This increases the odds of a viable pregnancy, but also of unintended twins, triplets, or further multiples. (Carrying multiple fetuses results in higher risk of prenatal, obstetric, and neonatal complications.) While several recent advances in IVF have led to an overall decline in this practice, one crucial discovery was the one by a research group at Stanford, in 2010, that careful visual observation of the transformation of single-cell zygotes into multicellular blastocysts can detect whether cyclin-CDK regulation is occurring as it should—simply by watching how quickly a cell moves from one stage in its dance of division into the next.

These observations predict, with roughly 90 percent certainty, whether an embryo is likely to progress toward viable fetus status. This breakthrough paves the way for more single-embryo IVF transplantations at higher success rates, without the risk of unintended multiple births. Within a few decades, Hunt’s measurements, gathered among the “shallow, rocky tidepools” of Cape Cod on the “spiny, globular creatures, with their erotic tongues of flesh,” have helped bring about the birth of human beings who otherwise might not have come into existence.

The Song of the Cell’s history of our understanding of what cells can do and what scientists can do to cells culminates in our present age, marked by our increasing ability to make “new humans” through pharmacological, mechanical, and genetic changes administered directly to cells and the still-tinier organelles at work inside them. “New humans,” in Mukherjee’s coinage, include not just those whose birth is made possible by these cellular technologies, but those whose ongoing well-being and survival depends on them, whether through deep-brain stimulation for neurologic or psychiatric illness, bone marrow transplantation that gradually alters every cell in the bloodstream, or mRNA vaccination that teaches the body to make a protein it did not previously “know.”

As with his Victorian-era counterparts like Edward Youmans, however, in Mukherjee’s science writing we find more than a neutral log of the era’s most salient discoveries and theories—assuming such a thing were possible. His work also points to some contemporary assumptions in biomedical knowledge-making and dissemination. First, there is the prevailing sense that scientific innovation is ineluctable and accelerating. In The Gene Mukherjee confronted our “headlong sprint into an abyss,” humanity’s rapid acquisition of tools for decoding and altering the human genome without the wisdom either to foresee the ramifications of this work or to resist the temptation to press on with it anyway. The very concept of the gene is, he wrote, “one of the most powerful and dangerous ideas in the history of science.”

In The Song of the Cell, the abyss remains in view. Mukherjee discusses He Jiankui, the Chinese scientist whose team used CRISPR technology to edit the genome of twin human embryos in 2017, deleting an immune system function that the HIV virus uses to enter the body, making the babies, whose father was HIV positive, resistant to the virus according to He. (Besides the grave ethical and methodological problems presented by He’s work, it should also be noted that existing antiretroviral medications, properly used, already render HIV effectively untransmissible between parents and newborns, and between any two people. The experiment therefore entailed no real benefit, but incalculable risk, for the humans involved.)

Whereas The Gene ended with a series of frantic questions—“Would such forms of knowledge [as genomic medicine] enable new kinds of empathy and understanding? Or would they nucleate novel forms of discrimination? Would the knowledge be used to redefine what is ‘natural’?”—The Song of the Cell is more resigned. “This is not to excuse [He’s] choices,” Mukherjee writes. “But…the genetic manipulation of the human embryo to arrest diseases (or, perhaps, to enhance human abilities) seems, every day, to become an inevitable destination for medicine.”

How inevitable is it really, though, and to which exact destination are we—should we be—heading? (That “or, perhaps” does quite a bit of work.) Mukherjee writes that settling on a “reasonable answer” will require an “evolving debate about the limits of scientific intervention, and the advancing front of cellular technologies. Every human is a stakeholder in this debate.” True enough, but without more specific thinking as to how and why we render our stakeholder status more than theoretical, every human’s vague right to register assent or dissent will remain no more than that, a license to sound off.

Books of popular science, insofar as they deliver the news of what is, what was, and what will be, often skirt what ought. In the same way, The Song of the Cell grows hazy when it comes to who or what ought to set the priorities of biomedical research—what problems to tackle further, or next. In current practice, these priorities are generally set by scientists and their home institutions, tilted by public-sector grants from bodies like the National Institutes of Health and sometimes by philanthropists and private-sector investors. Mukherjee closes the book by referring to the “moral vertigo” induced when the line between disease eradication and elective enhancement becomes ever blurrier. But how we might find our balance is not imagined in these pages. Alternative methods for setting priorities or creating new regulations when it comes to the new cellular medicine are not much discussed.

In another common tendency of the genre, Mukherjee’s accounts of biomedical innovation downplay or ignore the question of whether there might be other valid claims competing with biotech for a finite set of resources. Constraints of private or public budgets; of environmental impacts; or of rival social, medical, or public health priorities are minimally discussed. The other possibilities of a dollar (or a lab, or a worker’s time) remain unspoken. Amid all the excitement about what cancer immunotherapies (which often cost six figures a year, a sum shared between insurer and patient depending on the particulars of one’s plan), new techniques for organ and marrow transplantation (also six- or seven-figure endeavors), and still-newer feats of targeted genetic engineering can accomplish, it’s easy to forget that many cases of cancer, organ failure, or other diseases would be dramatically less prevalent—and thus not need treatment at all—if we as a society invested meaningfully in the obvious. Cleaner air, water, and nutritious food for all; free and accessible preventive medications and doctor’s appointments; affordable housing in which meals and medications could be safely stored and prepared, and where restful sleep might be possible. Though perhaps less alluring than tech innovations, these are the most significant means to improve human health.

The nineteenth-century Prussian physician and epidemiologist Rudolf Virchow cofounded the progressive newspaper Die Medizinische Reform under the ardent slogan “The physician is the natural attorney of the poor.” Mukherjee writes that Virchow’s early work in cellular pathology has proven to be more “timeless” than his later work in social reform, public health, and political activism. I am not so sure. When a history of biomedicine draws the eye primarily to flashes of conceptual ingenuity and technological brilliance, I worry that the physician-writer has neglected the opportunity to argue for what might be done right now, without a moment’s further research or a single new invention, for the poor and the sick of this very moment.

In a chapter devoted to the Covid-19 pandemic, Mukherjee shudders at the horrific image, widely shared across the Internet, of a migrant worker dying of respiratory failure immediately outside of a Delhi hospital, begging for a cylinder of oxygen. Mukherjee lists some of the causes of such appalling deaths—“a fraying, sclerotic global public health system, the absence of preparedness, misinformation…,supply chain issues…,strong-men leaders of nations”—but then ends the passage by coming back around to what he seems to find the most devastating shortcoming of all: that “just when we [scientists] felt that we knew the cell biology of the immune system,” we found that we did not. While I agree that a deeper understanding of the immune system’s cascade effect of lethal inflammation is wanted, this seems like a particularly technocratic response to the sight of a man desperate to breathe.

He goes on to describe how a group of Dutch researchers have found hereditary genetic mutations that affect the immune system’s ability to detect the start of a viral infection. In people with this mutation, the body fails to receive the necessary “danger signal” that would activate the innate immune system’s ability to rev up its response before infection has become too entrenched. Mutations such as these begin to teach us how viral infections like Covid-19, marked by substantial asymptomatic periods, trick the body by silencing such warnings, buying more time for the virus to replicate unchecked. More research like this may help us prevent the next viral epidemic from becoming a pandemic. So might other work, in arenas from public health education to electoral politics. “The pandemic demands autopsies of many kinds,” Mukherjee writes. The question of emphasis is all.

In many classic works of nonfiction, the writer’s relationship to their subject is skeptical, if not adversarial. The writer is not the subject’s friend or advocate: that job falls variously to marketing whizzes, executors, survivors, publicists. The writer’s earnings, too, come in the form of an advance and royalties—if they’re lucky—and end when readers stop buying the book. Imagine that Jessica Mitford, in addition to writing The American Way of Death, had cofounded a direct-to-consumer start-up to disrupt the old-school funeral industry. Or that you could have bought an ant farm directly from E.O. Wilson after reading Biophilia. Or that Annie Dillard was also a realtor selling parcels of the countryside she rendered so alluring.

It’s scarcely conceivable—yet today you can, in fact, choose to invest in the same food-tech start-up that Michael Pollan did, or pay for a “master class” with him on intentional eating. Or, if you were an employee of Amazon, Berkshire Hathaway, or JPMorgan Chase in 2018, you would have gotten the news that soon your health care would come from a company called Haven, with doctor-writer-CEO Atul Gawande at the helm. (Gawande stepped down as CEO in 2020, and Haven disbanded in 2021.) Or, if you have significant venture capital at your disposal, you might invest in Vor, or Myeloid Therapeutics, or Immuneel Therapeutics—three startups focused on genetically modifying stem cells and immune cells to enable their cancer-fighting potential, all co-led by Mukherjee. Rather than being particularly egregious, these examples seem symptomatic of our time: the waning era of the writer we encounter almost exclusively through their books, and whose primary expertise is writing. The new nonfiction writer is almost the opposite of the journalist: instead of standing outside their subject and looking in, this writer is openly an insider.

In his books Mukherjee mostly refrains from touting any products or techniques in which he is directly invested. When he pauses to marvel at particularly ingenious labs or innovations, they are usually the enterprises of others. (Verve Therapeutics, for example, his former coresident’s biotech company, attempts to improve people’s cholesterol levels by introducing gene-editing enzymes into their livers. Mukherjee calls this “the ultimate feat of cellular reengineering for heart disease.”)

At one point in The Song of the Cell, he does refer to creating genetically altered monocyte/T-cell hybrids to fight cancer, a technology that Myeloid Therapeutics is developing: in his lab, these cells “had eaten tumors alive. We are now growing these cells in massive numbers and testing all kinds of mechanisms by which they might be redirected against breast cancers, melanomas, and lymphomas.” Yet as Mukherjee’s achievements as a writer and start-up founder both continue to grow, I feel increasingly uneasy reading his work. I would argue that expository nonfiction in general—though particularly nonfiction that focuses on health and science—is long overdue for a renegotiation of the implicit contract between writers and readers.

One comes away from reading The Song of the Cell convinced, for example, that the modification of human cells and tissues through genetic tinkering is the inevitable, Janus-faced destiny of medicine: dangerous in the wrong hands, spectacular when managed by ethically sound scientists who are overseen by public consensus (though how is never quite clear). One also comes away convinced that a host of very important and potentially very lucrative innovations are coming out of Boston. Many a reader (who may also be a voter, investor, or policymaker) might well then breathe a sigh of relief that an already familiar and trusted writer happens also to be a scientist-entrepreneur—simplifying the work of choosing which ventures, from among the many available, to prioritize.

For Mukherjee, pure observation is one of the great motors of human progress. In The Laws of Medicine: Field Notes from an Uncertain Science (2015), for example, he discusses the astronomer Johannes Kepler, whose discovery that the planets have not circular but elliptical orbits arose because he was unwilling to simply wave aside—as his mentor Tycho Brahe did—observations of Mars’s transit that inconveniently contradicted the circular hypothesis. Kepler insisted on seeing what was there, until what was there at last made sense.

Santiago Ramón y Cajal, arguably the father of modern neuroscience, is another of Mukherjee’s heroes. Working in the late nineteenth century, Cajal arrived at his startling and crucial discovery that neurons communicate across the small gaps of synapses, rather than by direct touch, by making painstaking drawings of exactly what he saw under the microscope. His contemporaries and predecessors, less precise in their technique and expecting to see nerves touching nerves, saw only what they anticipated. Like Kepler, Cajal saw what was actually there. As Mukherjee has it:

It is one of Cajal’s legacies that he never performed a single experiment in cell biology—or at least an experiment in the traditional sense. To see his drawings of neurons is to realize how much can be learned by just seeing.

Like the Zen concept of shoshin (beginner’s mind) or John Keats’s notion of a poet’s “negative capability” being the avoidance of “any irritable reaching after fact and reason,” Mukherjee’s Cajal is a man who rejected the hypothesis-test-conclusion format of experiment and avoided guessing until he had observed. Cajal’s drawings, “as tenderly beautiful as they were forensically accurate,” serve as a kind of ars poetica for Mukherjee’s own project—to tell beautifully, and to tell truly, without allowing one’s preconceptions to place a thumb on the scale.

It is ironic, then, that in reality Cajal was no more immune from hypothesis-making or agenda-pushing than any of us. As Alec Wilkinson recently wrote in these pages about Benjamin Ehrlich’s biography of the Spanish neuroanatomist, Cajal made it his life’s work to definitively quash Freudianism and other hand-wavy invocations of “mind” (as opposed to “brain”), and therefore was prone to extrapolating from his own microscope observations in order to show that the organic brain was sufficient explanation for thought and behavior.^* He decided that the pyramid-shaped neurons he saw must be “psychic cells” responsible for consciousness, for example, because they are more abundant in intelligent mammals and humans. And his observation of synaptic gaps was made possible in part by his preexisting belief that a brain made up of fixed connections would not be able to learn or be “perfected.” Disinterested description is an elusive, perhaps an impossible, skill.

Virchow recognized that medical knowledge came from people full of inconvenient beliefs and judgments. “‘Science for its own sake’ is only a piece of rhetoric,” he said. “‘Science in itself’ is nothing, for it exists only in the human beings who are its bearers.” Good writing, good science, and good thinking certainly need not be analytical or argumentative. Yet very often they are. And in misclassifying such cases as pure, disinterested descriptions, we risk accepting arguments as though they were observations, the tendencies of our age as though they were permanent human values, and blind spots as though there were truly nothing to see in a particular patch of our medical and sociopolitical landscape.