Though we cut into the inside, we see but the outside of things and make but new superficies to stare at … Nature performs all her operations in the body by parts so minute and insensible that I think nobody will ever hope or pretend even by the assistance of glasses or other inventions to come to a sight of them.”
—John Locke
The frigid, metallic reality of the morgue at the University of Kansas is still disquieting to me, even as a veteran of over twenty autopsies. Instead of charging ahead into my third year of medical school, I have accepted a research fellowship in the Bone Research Laboratory with the world-class pathologist and researcher H. Clarke Anderson, MD. In addition to investigating cancer cell lines and bone morphogenetic proteins (BMPs, the signaling chemicals that initiate and control bone growth), I am obligated to take autopsy calls with Dr. Anderson. Here, in the dead of winter, I have been summoned to the morgue to investigate the cause of death in a local milk deliveryman.
The morgue is altogether different from the anatomy labs. As first year medical students, we became habituated to the cadavers in the anatomy room—their rigid, embalmed structures slowly revealing themselves to us in successive weeks. Every day, my two dissection partners and I would follow the instructions in our dissection manual and explore a particular anatomical detail in our cadaver, a seventy-four-year-old female. In time, the novelty of being surrounded by seventy corpses vanished, and questions of their backstories and humanity faded.
Arriving at the morgue, the thirty-eight-year-old, moderately obese and powerfully built deliveryman lies on the stainless-steel autopsy table, completely naked. The autopsy suite has three sturdy tables, purpose-built for autopsies, each with a central plateau pockmarked with irrigation holes and a circumferential trench with flowing water to wash away blood, body fluids, and the vestiges of infection and contamination. The subject is positioned on the central table, which is equipped with a foot-controlled recording device and microphone to capture the comments of the pathologist as the autopsy progresses.
Like every hospital morgue, this workstation is sequestered in the basement, away from foot traffic and patient care areas. The paucity of inhabitants and caregivers imbues a sense of loneliness and fear, even during the day. This is accentuated with the knowledge that dead bodies are stored in the lockers, refrigerated and ready for inspection. In the bowels of the hospital, with an ominous stillness and a monotonous ebbing of water over the tables, there is no lifesaving; there is only death-explaining.
Dr. Anderson explains that this worker was found outside his house in the early morning dawn, next to his running truck, facedown in the snow. An ambulance raced to his home, his grief-stricken and panicked wife overcome with anxiety and helplessness. After a failed resuscitation in the emergency room, he was declared dead by the ER physician and transported to the basement morgue. Every state has its own laws that guide the local coroners in deciding whether to order an autopsy; in this case, an unwitnessed death at home under unusual circumstances has prompted this man’s final physical examination.
We are dressed in blue scrubs and disposable paper gowns identical to those worn in the operating room. Waterproof gowns offer a layer of protection and a little bit of warmth, and protective eyewear is donned to keep body fluids from splashing into our eyes. Our simple tray of instruments ready, it is time to “see for ourselves,” the literal meaning of the word autopsy.
I place a gloved hand on the man’s torso, and he is unnaturally cold, the combined effect of him dying in the elements and his refrigeration in a cadaver locker for the last few hours. Dr. Anderson grasps the autopsy knife, outfitted with an impressively large blade made specifically for making the elongated cut in the front of the chest. I glance again at the decedent’s face, studying his contorted, bluish visage flattened on the right side from lying prone in the snow as he was dying. He was alive a few hours ago, but his rigid and motionless corpse looks counterfeit; only cutting into his barrel chest will convince me he’s a man.
The knife blade is placed at the sternal notch, the divot at the top of the chest bone where a thin layer of skin covers the windpipe. Cutting into the flesh, Dr. Anderson draws the knife in a straight line, down the front of the chest and along the abdomen, toward the belly button—and then taking a curved detour around it—and ending at the pubic bone.
Instruments are used to spread the skin edges apart, and I ready the bone saw to open up the sternum. I have learned how to use the saw, and Dr. Anderson allows me to operate the tool to cut the chest bone down the middle. This is the same device that heart surgeons use, and as a medical student, I’m thrilled to get to use real surgical tools years before I normally would. A rib spreader is placed between the bone edges, and winding a simple crank on the spreader forces the rib cage to gape wide open.
The heart and lungs announce themselves as the sternum is spread. The crimson-colored muscular heart is partially shrouded by the billowy lungs; gray, diaphanous, and boggy. The heart and lungs are bound together, yin-and-yang, different in color, structure, function, and heaviness. The thoracic cavity, demarcated as a cage of bony ribs and floored by the muscular diaphragm, encases the heart and fragile lungs. The diaphragm is a thickened, powerful membrane that partitions the thoracic and abdominal cavities. The diaphragm has three large, inch-wide holes that allow passage of the esophagus, aorta, and vena cava. By carefully cutting through the fleshy diaphragm, we can preserve the integrity of the vessels and esophagus, not causing leakage of blood or food contents.
Once in the abdominal cavity, we encounter the liver, the size of a small football, the kidneys, the intestines (stomach, small intestine, and large intestine), the spleen, bladder, and pancreas. Because the walls of the intestines have not been carelessly cut, there is no spillage of partially digested food, or further along the tract, in the large intestine, feces.
As medical investigators, we have several choices in how we examine these organs. The most old-fashioned method would be to simply poke around, handle the organs with our hands, and use our powers of observation to guess what hastened death.
A more advanced technique would be to cut out the organs as they lay in the thoracic and abdominal cavities. With the Rokitansky method, groups of organs are removed at once, and inspected on a side table. Virchow’s technique is to remove the organs one by one in situ, cutting into them and preparing tissue samples for microscopic analysis, a dramatic leap forward compared to manual manipulation alone.
Today, we will use a technique that, indelicately stated, reminds me of how I learned to “gut a deer” while hunting with my father and brothers on our family’s ranchland in Wyoming. The Letulle technique involves exposing all the organs and intestines from throat to anus, and dissecting them cleanly away en masse. While cutting away the soft tissue connections from the cavity walls, the pathologist lifts out the heart and lungs, all the intestines, and all the abdominal organs while still maintaining all the connections to each other; what remains are hollowed out, empty cavities. On the dissection table, all the organs are much more easily evaluated, with easy inspection of every aspect of every organ, since they are no longer tethered down to the body walls. This method is favored by my mentors, and no doubt arose from someone who was from a hunting family.
After removing the mass of organs and tissues, Dr. Anderson and I struggle to transport the slippery jumble of tissues onto the dissection table. Here, we slowly start to cut into the organs, looking for gross abnormalities. Small tissue samples are collected, and we plop the masses into small plastic containers with labels, filled with formalin, and screw on the orange lids.
The head is approached last. The hair on top of the corpse is divided, and after making a long incision along the top of the skull, the skin is easily peeled down on either side, exposing the skull. A specialized saw is used to cut the bone all the way around the top of the skull, and after chiseling away the final soft tissue connections, the membrane around the skull is encountered—smooth, thick, and opalescent. This is the dura mater (Latin: tough mother), and after cutting through it, the brain is encountered. Severing the nerve connections and the spinal cord at the bottom of the brain, the gelatinous mass is lifted out by Dr. Anderson, and he (unbelievably) hands me an entire human brain.
The brain of this gentlemen is firm and pink, robustly characterized by circuitous folds and wrinkles that shrink with age, but in this young man are so plump it seems that his brain was too big for his skull, stuffed in by the promethean life-giver. Inspecting the brain matter with duteous fingers, pushing the gyri this way and that, peering into the sulci, and investigating for ruptured vessels or evidence of tumors, we satisfy ourselves that a gross examination of the organ reveals no immediate abnormalities.
Standing opposite each other over a narrow table, Dr. Anderson and I stabilize the brain with our hands. He grasps a twelve-inch-long knife that looks suitable to carve a turkey, and begins slicing the brain like a loaf of bread. Each slice of brain is about a third of an inch thick, and we lay out the sections on a large pan. This results in a tray full of brain slices, almost like a pan of large cookies, permitting thorough inspection of the entire brain. This technique was developed decades before there were CT or MRI scans, and was the only way of delving deeply into the brain structure of deceased individuals.
Having harvested all the organs and intestines, we turn again to his heart. Everything else normal, our suspicions center on acute myocardial infarction, or a heart attack. With a massive heart attack that results in immediate death, there are no grossly visible (to the human eye) changes to the heart muscle. In someone who has battled cardiac ischemia for days prior to death, the myocardium begins to turn pale—even yellow. In our deliveryman, the heart looks normal, but now we focus on the coronary vessels.
The heart is our body’s pump station, and even though all of our blood comes pulsating through the cardiac chambers, it doesn’t perfuse the pump’s muscle. The cardiac muscle demands its own vascular supply, coming in the form of the coronary arteries that branch off the aorta as it leaves the heart. These two main arteries, the right and the left, branch out and send little arterioles deeply into the muscle to provide oxygen and fatty acids (used as fuel). The coronary arteries are visible on the exterior of the heart, and using surgical instruments, we dissect the arteries for microscopic analysis.
In our hearts, the left coronary artery bifurcates into two main branches, just an inch from the aorta, and these two branches feed the most important part of the heart, the left side, which must powerfully contract to propel blood to the entire body. Dissecting further, we isolate the left anterior descending artery (the LAD, or “widow-maker” artery), and cutting it free, take the two-inch-long, spaghetti-thick vessel and dunk it in formalin. It felt rigid and crunchy, and Dr. Anderson’s thoughtful and pensive gaze at me remedies an investigator’s vehement skepticism about the cause of death for this man. I think he knows we have found the killer—a dislodged cholesterol and fatty clot that blocked this most important, if not proportionally sized vessel—and his sensitivity for this man and his family overcomes scientific dogma and pathology.
After “fixing” the small bits of tissues overnight in their formalin cups, the samples are further dissected and we place the critical samples into small blue plastic cassettes for microscopic preparation. These little cassettes are about the size of Tic Tac containers, and are loaded into a machine that exposes the contents to increasing concentrations of alcohol, half an hour at a time, and then xylene, with the aim of halting all cellular degeneration or bacterial growth while removing all the water and fluid in the original tissue samples. The apparatus then dunks the plastic cassettes into paraffin, creating a microscopic time machine where the tissue samples have been frozen in time in a chunk of white wax.
I hand the stack of waxy blocks to our lab tech, who loads them onto the Leica microtome, a machine that creates extremely thin wafers of wax that come reeling off the blocks in a little chain, like paper Christmas ornaments. She mounts the wax sections on glass slides, which are then taken to the staining station. Until the dark purple and red stains of hematoxylin and eosin (H&E) are applied, the tissue slice on the glass slide is nearly invisible, but in time, the tissue section will pop with clarity and differentiation. The tech picks up the slide and begins dunking it into small metal cups of chemicals and dyes. Sometimes for thirty seconds and sometimes for less, she works her way down the row of cups, and after drying, the slides are ready for viewing.
I can’t resist the urge to look at the slide of the widow-maker coronary artery first. I position the slide on the microscope stage—the little platform on my Zeiss microscope with a hole in the middle—that allows for the light to pass from underneath. Lowering my head over the eyepieces, I rotate the focus ring until the cells come into clear view. The artery, cut in cross section, is completely occluded with thrombus and atherosclerosis, and I am staring at my patient’s killer, the very real representation of a heart attack, frozen in time. This clot prevented precious blood flow to the most critical part of his heart, and deprived of fuel and oxygen, the cardiac muscle ceased to pump, leading to his collapse in his driveway.
Death and disease had been shrouded from humanity’s comprehension from our earliest reasonings; in the span of a few generations my forefathers used discipline, skepticism, the microscope, and chemical dyes to lift the veil and unlock the secrets of illness. Here in the morgue, armed with the tools of the pathologist, I can explain, scientifically, why this man died, even if I can’t comprehend how precarious our existence is.
By the mid–17th century, Padua, Italy, could lay claim as the crucial birthplace of knowledge and learning of the Italian Renaissance, even outshining the University of Bologna, the oldest university in the world. Sons of Padua included Vesalius, Falloppio, Harvey, and Galileo, and as the 18th century approached, a recent graduate from the University of Bologna school of medicine arrived in Padua, consumed by a lifetime devotion to a project that would seismically change medicine forever.
Giovanni Battista Morgagni (1682–1771) graduated from Bologna at the age of nineteen, soon forming an intellectual society for students and new graduates called the Academia Inquietorum—Academy of the Restless. As a new graduate, Morgagni had encountered a new book by Theophilus Bonetus the Sepulchretum, a compendium of thousands of cases of clinical histories and correlative autopsies. These were compiled by Bonetus from the burgeoning medical literature by a vast array of authors that, unfortunately, was disorganized and haphazard, rendering it almost unreadable. The young Morgagni “nevertheless, pored over the Sepulchretum … and it became clear to him that because the concept upon which it was based epitomized a fundamental truth,”1 set about (at first) revising the book, but later constructing an entirely new work based upon his own cases.
Morgagni began his project as a newly minted physician, probably twenty or twenty-one years of age, and began collecting information on the patients he was treating and the results of their autopsies. One by one, he built a compilation of cases, with careful observations, astute clinical interpretations, and the occasional physiological experimentation to bolster his clinical conclusions. “To this enormous undertaking he brought his considerable talents as a practicing physician, his towering preeminence as an anatomist, his resourcefulness as an experimental physiologist, and his infinite patience with detail.”2
How patient was Morgagni in preparing his book? While treating his patients in Bologna and Padua, he spent the next six decades collecting information, organizing the material, and writing the book that would change the way that physicians looked at patients and thought about the essential nature of disease. Morgagni published his book De Sedibus et causis morborum per anatomen indagatis (Of the seats and causes of diseases investigated through anatomy) in 1761 at the advanced age of eighty while still treating patients.
De Sedibus is written in conversational style, as if to a friend, and is organized into seventy letters to a young physician (perhaps fictional). The sum total of these seventy letters encompasses seven hundred cases, and is organized into five books: Diseases of the Head, Diseases of the Thorax, Diseases of the Belly, Surgical and Universal Disorders, and Supplement (including index). For each case, “historical background is given, the evolution of contemporary thinking is reviewed, authorities are quoted, their opinions discussed, and the logical development of the professor’s conclusions, step by step, become clear.”3 Compiled over decades, the cases are meticulously organized and indexed, so that a young student could search the book by symptom, such as “chest pain,” and investigate a similar case, searching for truths and possible effective treatments.
One hundred years earlier, Galileo had challenged the unscientific and superstitious view of the heavens. Morgagni occupied a world where physicians throughout the world were still ensnared in the ancient Hippocratic traditions, perseverating over humors, the seasons, miasmas, bad air, and celestial judgements. Morgagni’s De Sedibus dealt the final death blow to humoral medicine, and turned the mind of the physician to “specific derangements of particular structures within the body.”4 The anatomist and physician Morgagni concluded, in perhaps the most iconoclastic statement in medical history, that symptoms were quite simply the “cry of suffering organs.” Succinctly and beautifully captured, this new appreciation of disease focused the attention of the physician on a particular organ or body part. Instead of gazing at the stars or considering imbalances of mysterious fluids, Morgagni realized that disease was the manifestation of dysfunctional (and often painful) organs.
Hundreds of cases over the course of sixty years had convinced Morgagni that disease followed observable patterns. In the 1700s, pharmacology was in its nascence; physicians (and especially surgeons) were largely impotent. But Morgagni was gaining insight about organ-based illness, and with experience, he could predict what he would find at autopsy. He probably saved not one life, but as the decades passed, he grew confident that he could predict what he would encounter at the autopsy table. De Sedibus was quickly translated into French, English, and German in the same era of the American Revolution; the United States was born at the same time that physicians around the world were concluding that a constellation of symptoms were pointing to a specific ailing organ.
A truism exists regarding advances in medicine: to best comprehend how an organ (and its constituent cells) actually function, evaluate the organ following an injury or during disease. Descartes had proposed that the human body was merely a machine; Morgagni’s influence was to view the coordinated physical-mechanical structures (that normally worked in faultless harmony) as a watchmaker or machinist whose job was to diagnose faulty parts. Physicians would now be in the business of carefully listening to the cries of sick organs, fastidiously observing and examining patients, and then empirically theorizing about what was killing them.
Morgagni is not simply the father of anatomic pathology, but also the figure who is credited with initiating modern medical diagnosis. “The full consequences of what he worked out were harvested in London and Paris, in Vienna and in Berlin. And thus, we can say that, beginning with Morgagni and resulting from his work, the dogmatism of the old schools was completely shattered, and that with him the new medicine begins.”5 It seems odd that we don’t know his name better, but Morgagni is among the most important figures of the Enlightenment. His disciples include Jean-Nicolas Corvisart (1755–1821) and Pierre-Charles-Alexandre Louis (1787–1872), physicians who helped establish Paris as the mecca of medicine in the 19th century. The pendulum would eventually swing back toward the east, when a critical physician from Vienna fully adopted the concepts of the pathologic basis of disease, performing over 30,000 autopsies in his career, all without the most powerful tool in the history of medicine.
A wave of political upheavals pulsed across Europe in 1848, affecting almost every European country and many of their colonies worldwide. This revolutionary activity challenged feudal lords and royalty, establishing greater democratic rights for the lower classes, even witnessing the introduction of The Communist Manifesto that same year. In particular, the revolutions in the German states and the Austrian Empire had significant repercussions in medicine and academia, much like American college campuses in the 1960s. The stodgy, outdated lords of medicine held off revolutionary-minded fledglings in Vienna; the battle of the “new versus the old, the intellectually liberal versus the conservative, the true scientific understanding of disease versus the fuzzy theoretics of the old medicine” played out at the University of Vienna’s school of medicine. The chief agitator was the Bohemian Carl von Rokitansky (1804–1878).
Rokitansky grasped the significance of Morgagni and his French devotees, digging deeper and searching indefatigably for the root causes of disease and death. The more he studied disease, the more profound was his understanding of function. If Morgagni is the father of anatomic pathology and medical diagnosis, then Rokitansky is the man who literally built the house of pathology.
The Allgemeines Krankenhaus (or General Hospital) now exists as the University of Vienna undergraduate campus, but the expansive courtyards and stately buildings remain intact, even if they are filled with Bohemian Austrian students and not suffering patients. In the northwest portion of the campus stands the Center for Brain Research, an imposing three-story stone building on Spitalgasse, guarded by a brick and steel barrier and topped by a grouping of Greco-Roman figures and the Austrian double eagle shield. Below the figures is a gold-embossed inscription in Latin that is the only indication that this building used to serve a completely different function. Fifty feet overhead, one can read INDAGANDIS SEDIBUS ET CAUSIS MORBORUM, an obvious nod to Morgagni’s revolutionary book, meaning “Investigation of the seats and causes of disease.” This was once Rokitansky’s Pathological Institute, a concert hall of medicine, where he demonstrated over 30,000 autopsies in his long career.
The structure and organization of the institute, where every single patient who died at the general hospital was examined postmortem, helped relocate European medical leadership to Vienna. A collection of physicians came together in Vienna to birth the specialties of pathology, dermatology, psychiatry, ophthalmology, and surgery, and Rokitansky’s influence on the young physicians’ method of clinical reasoning and scientific observation was significant. Behind the Institute is a purpose-built lecture hall where Rokitansky could lecture and demonstrate, and where the legendary Viennese surgeon, Theodor Billroth operated (as depicted in the painting by A. F. Seligmann, displayed in the Galerie Belvedere in Vienna).
It is astonishing to consider that Rokitansky performed those thousands of autopsies without a microscope. Like realizing that Copernicus had no telescope, Rokitansky performed all of those autopsies grossly, with simple manual examination of the organs and tissues. This severely limited his ability to take the conceptual leap about what caused disease, but his significant world leadership is without question. Physicians, like their astronomy brethren, needed to magnify their objects of interest to see further and illuminate their minds. It would take a few serendipitous findings to turn microscopy into a formidable tool, powering the greatest biologic insight of the Enlightenment.
At the genesis of the Royal Society, the microscope took center stage. The problem solver, tool builder, and skeptic Robert Hooke published his groundbreaking Micrographia in 1665, just a few years after the Society had been founded. The book was the first major publication that included depictions of microscopic views, shattering assumptions about the unseen world. Hooke was an expert draftsman, and his drawings fascinated readers and agitated the imaginations of his fellow geniuses around Europe. Perhaps most famously, his drawing of a flea, produced in his book on a massive foldout sheet, showed every minuscule hair and shingled plate that revealed the flea not to be a tiny, gnat-like, defenseless creepy-crawly, but instead a body-armored miniature beast with a carapace. Size matters, but microscopists were poised to reveal that structure reveals function, and although it would take another two hundred years to firmly prove the point, it is the tiniest living beings that pose the greatest threat to mankind. Hooke’s flea was the ideal object to focus man’s attention to the microscopic world, just big enough to be visible to our naked eye, but small enough that all detail was out of reach, safely in its hirsute haven. Through a strange coincidence, just as Hooke was illuminating the character of the flea, the last great plague was terrorizing London in 1665; only later would it come to light that the flea was the carrier of the plague bacteria, and innocently, Hooke might have been playing with fire in his dissections and depictions.
Hooke spent considerable time investigating the structure of plants as well. His microscope had just the right amount of magnification for him to detect the minute building blocks that comprised the organization of the plant—coining the term cell for the little “rooms” he saw in the microstructure of cork—and the term would be adopted for all plant and animal microscopy going forward. The cellular basis of life would not be uncovered until the mid–19th century, and it would take modern chemistry to make it real.
Most of us have an image that immediately pops into our mind at the mention of the word “microscope.” It is a tilted black metal tube mounted on a U-shaped stand, holding a glass slide on a platform. Today, of course, there is an electrical cord that supplies the energy for the light bulb at the bottom of the microscope, illuminating the slide from underneath. There are also focus rings and adjustment knobs to move the platform and glass slides. This has been the form of the microscope for centuries, but the world’s first microscopist Antoni van Leeuwenhoek had a “bead microscope,” a seemingly bizarre and limited tool that actually allowed him to see living cells in a way that no one ever had.
Leeuwenhoek was a Dutch surveyor and cloth merchant, and was used to using a telescope to see distant landmarks and a magnifying lens to count threads in material (this brings to mind the “thread-count” in sheets). Utilizing a single, tiny glass bead with a highly convex edge and placing it on a small metal paddle, Leeuwenhoek was able to view tiny objects held in place with wax on a needlepoint very near the glass bead. Small screws permitted movement of the object up and down, and forward and backward. For decades, he corresponded with the Royal Society, submitting drawings of the microscopic world, describing the unseen that had been revealed to him with his primitive yet practical tool.
Leeuwenhoek initially published articles in the Royal Society’s Proceedings about bee stingers, lice, and the hidden world in a drop of pond water, but within a few years, published a work on the startling appearance of sperm. In 1677, he wrote to the Royal Society, offering his willingness to submit a paper, “If your Lordship should consider that these observations may disgust or scandalise the learned, I earnestly beg your Lordship to regard them as private and to publish or destroy them as your Lordship sees fit.” By 1678, he published his article on the nature of the “seed from the genitals of animals,” including drawings from the sperm of rabbits and dogs, taking special care to write that when he examined his own semen, “That what I am observing is just what nature, not by sinfully defiling myself, but as a natural consequence of conjugal coitus … ”6
The truths of conception had been debated for thousands of years, and the early microscopists eagerly sought to investigate what the constituent parts of semen looked like. It was too difficult to determine what was happening in the interior of the womb for these primordial scientists, but the specter of the wriggling sperm, so similar to a tadpole or the microscopic protozoa, all equipped with flagella for propulsion, was a verity that had been guessed at since humans had been able to ponder, “Where does life come from?” Just as important, the sperm did not look like miniature animals ready to travel into a uterus. (At the advent of microscopy, many wondered if they would find little puppies or kits in the cells of dogs or rabbits.) The travelers, instead, looked like purpose-built little machines, ready for a voyage into the womb, even if their mechanism was hidden from the virtuosi’s insight.
As microscopy improved, an amazing transition occurred. As Bacon had predicted decades before, the sequence of innovation would be to catalogue, then sift, and then, with “suitable application of intellectual machinery,” to arrive at a knowledge of invisible structures.7 As Catherine Wilson argues, “science destroys the image of the familiar world and substitutes for it the image of a strange one, wonderful to the imagination and at the same time resistant to the projection of human values.”8 As new realities came into view, scientists were forced to change ancient conclusions and adopt new theories, but strangely, after a feverish half-century of microscopic discovery, a lull settled over the minds of the investigators of the infinitely small.
Regarding imagination, the Enlightenment author Bernard de Fontenelle’s philosopher-hero observes that “… our minds are curious, and our eyes bad … we wish to know more than we can see … Thus do true philosophers pass their lives, in not believing that which they see, and in endeavoring to divine that which they see not.”9 The development of clear glass, the innovation of lens manufacture, the assemblage of compound microscopes, and the wide-ranging publications of the microscopic illustrations eventually led to complacency. How many doodles of fleas, sperm, and insect eyeballs can you stare at? By the late 18th century, microscopy stalled, even as the Industrial Revolution was exploding across the world. To comprehend just how passé microscopy had become, consider that the revolutionary Carl Rokitansky conducted 30,000 autopsies without ever attempting to examine the tissues with the one instrument that could have utterly transformed his practice. Some science writers, like David Wootton, have pondered why 17th- and 18th-century physicians and scientists were unable to advance tissue microscopy, but there is a rather obvious explanation for pause of advancement: the lack of dependable dyes that had the power to bring the tissues to life.
If we were together right now in a pathology laboratory, we could dissect and prepare tissue for microscopic evaluation, settling upon a step where the extremely thin piece of tissue was mounted on a glass slide, ready for viewing. If we mounted that slide on a microscope platform and switched on the light, we would peer down the compound lens tube and see a faint outline of cells and supporting tissues, but with almost no ability to discriminate or comment upon the structure or function of cells. If you had never seen a painting of Van Gogh’s Sunflowers, and I presented you a low-resolution black-and-white rendering of his poignant and melancholy artwork, there would be little impact. Conversely, an intimate experience, face-to-face, with Vincent’s canvas, confronted with the turquoise and Tiffany-blue background and stunning canary and butterscotch yellows of the petals, painted with heavy brushstrokes of dolloped pigments, you would agree that Van Gogh had achieved a “symphony in blue and yellow.”10
Those who would criticize the microscopists of the 17th and 18th century would do well to remember the paucity of color and the lack of electric lighting during that epoch; while there were simple plant dyes, chemistry before the mid–19th century was so limited that chemical reagents for trial-and-error experimentation did not exist. A happy accident in the east end of London would bring color to an otherwise drab, scientific world.
Antoine Lavoisier (1743–1794) was a scientific genius, committed to methodically analyzing chemical reactions and determining why fires burned, why we breathe, and why substances react. After fastidious experimentation and thoughtful analysis, he reinforced the notion of the conservation of mass, saying, “Nothing is lost, nothing is created, everything is transformed.” If he doesn’t hold the sole title as the Father of Chemistry, he is the Father of Stoichiometry, the concept that chemical compounds are composed of molecules in exact ratios, and that new compounds can be formed via chemical reactions, either into larger novel compounds or smaller constituent molecules.
Lavoisier, a nobleman who profited dramatically from the inequities of the old French aristocracy, was the first person to organize a list of the elements and to develop a language of scientific nomenclature to describe the building blocks of the physical world. Like a trained chef who understands the uses of baking powder, baking soda, sugar, and eggs, Lavoisier was beginning to grasp how the elements interact with each other and why metals rust, and how plants take in minerals from the soil and chemicals from the air. His genius insight was to view the world as amalgamated from its ingredients, its atoms, and he influenced his French and European followers to conclude that the world could be described by its building blocks. (Sadly, Lavoisier did not survive the French Revolution, beheaded at age fifty. One of his pupils did escape to America before suffering a similar fate: Éleuthère Irénée du Pont, patriarch of the chemical dynasty.)
Before the periodic table could be formulated (by Russian chemist Dmitri Mendeleev in 1869), a chance discovery before a “prepared mind” helped transform grammar-school chemistry into a specialty on par with mathematics and physics. William Henry Perkin entered the Royal College of Chemistry in London as a fifteen-year-old in 1853, and although Lavoisier is the pioneering giant of chemistry, young William made a discovery in his flat in East London that set in motion modern chemistry and revolutionized biology, medicine, and the pharmaceutical and fashion industries.
Tasked by his professor at the college to synthesize quinine (the only effective anti-malarial at the time), Perkin returned to his home on Cable Street in London’s Shadwell area with reagents, flasks, and instruments in hopes of creating the prized drug originally sourced from a South American tree. On Easter break in 1856, by himself in a home laboratory, the eighteen-year-old Perkin started with the basic ingredient, coal tar, a black liquid byproduct of heating coal in the absence of air. Coal tars were a common waste product in the new Industrial Revolution, and Perkin began oxidation experiments with the mucky stuff in his upstairs flat. Finding no success, he added potassium dichromate, creating a dark watery precipitate. While cleaning out his flask with ethylene alcohol, the precipitate turned a dark purple, which he initially named “Tyrian Purple,” later changing the name to “mauve.”11
Purple has been the color of royalty for millennia, and in Roman times, twelve thousand mollusks were required to produce enough Tyrian (Phoenician) Purple to dye a single dress the size of a Roman toga. Other plant-based dyes had been tried but always faded. Perkin immediately realized the value of his discovery, performing experiments on the “fastness” of the dye. Perkin had discovered a durable, inexpensive, yet highly desirable material from rubbish, and quickly applied for a patent. By the time he was nineteen, he opened a dyeworks outside London, massively profiting from his serendipitous finding. Alchemy, apparently, was possible after all.
The real mother lode in Perkin’s discovery was not in coloring clothing, but something much, much bigger. Chemistry evolved into an industrial discipline, with chemists scrambling to create other colors from coal tar in hopes of cashing in like Perkin. In a surprising twist, the chemical experimentation led not to new dyes but to new molecules that had biological effects. One of the early products created with the new learning was N-acetyl-p-aminophenol, today known as Tylenol. From the nascent synthetic dyes industry exploded new knowledge about chemical reactions, with enormous advances in medicine, photography, perfumery, food, and explosives.
The improved understanding of chemical structures led to massive growth of European companies with chemical expertise, particularly in Germany, where companies such as BASF, Bayer, Agfa, and Hoechst were founded. The modern pharmaceutical companies were born in short order, starting in the 1880s; some of them (like Merck) had existed for years as apothecary shops, peddling plant extracts, but the new understanding of synthetic chemistry transformed the companies into major industrial chemical research entities. Previous small concern companies like Schering, Burroughs Wellcome, Abbott, Smith Kline, Parke-Davis, Eli Lilly, Squibb, and Upjohn all metamorphosed into giant companies rushing to create new medicines.12
The quiescent field of microscopy, where little progress had been achieved in over two hundred years, was poised for an awakening. “Because good fixative, paraffin embedding, microtome and eosin stain were not available prior to the 1860s, pioneer microscopic pathologists most often obtained their specimens for microscopic examination by scraping and teasing out the cut-surface of tissues or by preparing smears from fluids and aspirates.”13 Little wonder that the first breakthrough observations of the 1830s and 1840s would be achieved when sampling blood and skin.
With the German openness to dyestuffs and chemical experimentation, it was natural that microscopists would start to tinker with tissue dyes. Scientists were used to altering chemical protocols in order to achieve better color penetration and colorfastness in cloth, and it was only a matter of time until the right recipe would be determined for medical use. There were essentially no worthwhile stains for microscopic slides until the decade after Perkin’s discovery, and it was another South American plant that garnered attention. The logwood tree, Hematoxylon campechianum, is an indigenous tree of the New World whose roots and trunk exude a ruddy turbid colorant when boiled or steamed,14 and was used for centuries as a dye for cotton. The Spanish used the dye (as did the Mayans), and also American soldiers during the Civil War.
A century and a half ago, hematoxylin was identified as a potent mammalian tissue stain, causing a bland, colorless tissue sample to adopt a deep purple, india ink–like hue. Experimentation with various chemicals added to hematoxylin yielded a combination that readily stained the inner parts of the cell, later revealed to be the nucleus, where the chromatin (DNA and RNA) is housed. A decade later eosin, a reddish-pink dye, was discovered as another dye that readily attached to other cellular structures, yielding a fuchsia shade over the entire representation. While the newly discovered dyes provided much improved visualization of the material, it was like looking at a coloring book pigmented with only one crayon.
Washing the slide material with alcohol and other drying agents led to visual changes in the tissues, and a scientific game of hide-and-seek transpired as the German histologists played with the sequence and timing of chemical exposure. A double-staining technique using two stains in succession, and, finally, the combination of hematoxylin and eosin in 1876 set the standard that is still used everywhere today.15
The combination of hematoxylin & eosin (H&E), with almost three million slides per day prepared in the cytopathology labs around the world, must be regarded as one of the most monotonously successful chemical combinations on earth. All the chemical and pharmaceutical advancements achieved since the modernization of medicine have not changed the fact that the two chemicals in H&E staining are perhaps the most reliable molecules in medicine, touching more lives over the last 150 years than almost any drug. The yin-yang of H&E staining meant that various elements in tissue were reliably stained either pink or deep purple, and researchers could now focus their eyes on the individual cells that made up organs.
While the birth of industrial chemistry occurred in England, it rapidly found a home in German academia, and the multiple scientific bastions that would prop up medicine in the future—optics, pharmaceutics, engineering, physiology, and radiology—co-evolved with decidedly German sensibilities as well. The Italian leadership in medicine, most recently championed by Morgagni, had resulted in a renaissance of French medicine that turned physicians’ attention to the patient and her symptoms. Viennese medicine was at the forefront of the birth of many specialties in the mid–19th century, and Rokitansky, the last great naked-eye pathologist, tutored many accomplished physicians around the globe. But the Germans embraced all the new sciences with such gusto and with a cultural alignment that made full adoption of the scientific leadership mantle unquestioned. The title of ascendency among physicians in the world would pass from Rokitansky to a maniacal worker and savant in Berlin, a man who embraced the microscope, with its dyes and German-made lenses (like Zeiss and Leica), and who established the concept of the cellular basis of disease.
There has scarcely been a medical student and young physician who labored harder than Rudolf Virchow. The eager young Virchow was born in Pomerania in 1821 to a farmer and local treasurer and after graduating at the head of his class in 1839 from the local secondary school, enrolled in medical school in Berlin, in a military unit of the University of Berlin. Here, at the Friedrich-Wilhelms Institut, Virchow was tutored by Johannes Müller, “a biologist, comparative anatomist, biochemist, pathologist, psychologist, and master teacher,” who trained generations of great German physicians. Müller began his career as a physiologist, focusing on nerve function, the mechanism of retina, and the functions of the sense organs in the ear. As happens in science, the objects of interest become increasingly small, and Müller’s early subject matter was at the extreme boundaries of plain-vision investigation.
Müller had legendary energy (perhaps suffering from bipolar disorder, exhibiting bouts of mania and, alternately, severe, incapacitating depression16) and tended to attract like-minded and similarly indefatigable pupils. An early student was Theodor Schwann (1810–1882), who became the principal advocate of the cell theory newly proposed by his botanist friend Matthias Jacob Schleiden (1804–1881). Together, the works of Schleiden and Schwann in the years 1838 and 1839 set a firm foundation for the new appreciation of the importance of cells in plants and animals, explaining how they grow, function, and interact. Chemistry had the atomic theory; biology now had the cell theory.
Müller rapidly turned to the microscope in 1838, and soon was examining the cellular structure of tumors microscopically. Into this torrent of activity and revolutionary upheaval in 1839 strode the new medical student Rudolf Virchow. It was like two supernovae colliding, and the explosion of insight and output is almost unrivaled in scientific history.
Rudolf Virchow was incredibly intelligent and monstrously energetic. He was fluent in many European languages, and had learned Greek, Latin, Hebrew, and Arabic. Besides his multilingualism, he was an ardent archeology, ethnology, and political science devotee. At age twenty, he wrote his father from Berlin that his aim was to acquire “no less than a universal knowledge of nature from the God-head down to the stone.” The brash and ultra-confident German, short and thin with bespectacled dark eyes and a piercing owl’s gaze, wrote shortly before medical school graduation, “… you misunderstand me if you think my pride is based on my knowledge, the incompleteness of which I can see best: it is based on the consciousness that I want something better and greater, that I feel a more earnest striving for intellectual development than most other people.”17
Virchow graduated medical school in 1843, initially working at Berlin’s Charité Hospital, associating himself with the pathologist Robert Froriep. Within two years of graduation, in 1845, Virchow published a case report of a cook in her mid-fifties who had died in Berlin from an unknown disease. At autopsy, the blood in her organs contained a thick, milky layer, floating like a waxy blob. At first glance, it must have appeared like pus to the twenty-four-year-old physician, but unlike John Hughes Bennett, the Scottish physician who first described the disease four months before Virchow, Virchow did not declare it a “suppuration of blood,” or an infection. Smearing the blood on a microscope slide, utilizing the primitive carmine dye to stain the cells, and carefully observing the constituents of the fluid, Virchow was at a loss to explain the phenomenon of the hordes of large round cells (interspersed among the small red blood cells) he was observing, and decided upon simply describing the disease by its visual appearance: weisses Blut (white blood). In a subsequent 1856 publication, Virchow adopted the Greek term for white blood, leukemia, including the description of two forms of the disease, one in which the spleen is enlarged and the other in which the lymph nodes are infiltrated by the white blood cells.
Virchow published another article in 1846 on the nature of blood clots, proposing theories about the genesis of deep venous thrombosis (large blood clots) and emboli (traveling blood clots) that have proven true all these years later. The twenty-five-year-old decrypted the enigma of embolism, where a large blood clot detaches from a leg or arm vein and travels to the lungs, where it completely obstructs blood flow and causes catastrophic death, a concept no one had ever considered. In the space of a year, Virchow had correctly identified (and even postulated the cause of) two major diseases that had plagued mankind forever. Bolstered by his success, Virchow decided to publish a journal, The Archive of Pathological Anatomy and Physiology, and Clinical Medicine. It is still published to this day, as one of the most important journals in the world; it is simply referred to as Virchows Archiv.
In the first issue, Virchow outlined his scientific world view in a tour de force statement. He declared, “Pathologic anatomy is the doctrine of deranged structure; pathologic physiology is the doctrine of deranged function … [t]he science of pathologic physiology will then gradually fulfill its promise, not as a creation of a few overheated heads, but from the cooperation of many painstaking investigators—a pathologic physiology which will be the stronghold of scientific medicine.”
As has been seen repeatedly in this work, the Europe-wide Revolutions of 1848 had broad scientific, political, and artistic implications. Virchow was swept up by his ideals of social medicine, which destabilized his position in Berlin. Finding a new home in nearby Würzburg, Virchow entered the most productive epoch of his life. He tackled the subjects of inflammation, cancer, kidney disease, and the anatomy of the skin, nails, bone, cartilage, and connective tissue.18 Lacking electricity, photomicroscopy, and projection of images, Virchow invented the “table railroad,” a track that passed microscopes from student to student so they could peruse what the master wanted them to examine. He implored his scholars to “see microscopically” and to adopt his view that the cell was the fundamental unit of life.
After almost a decade in Würzburg, Virchow returned to Berlin in 1856 with great fanfare and to a purpose-built pathology institute. His time in Würzburg had resulted in several quantum leaps in the understanding of cellular function and behavior. Sometimes adopting the ideas of other German researchers, the influential Virchow made ever-increasing claims about the primacy of the cell, at first (in 1852), declaring that any new cell can only arise from the division of a cell already present; in 1854 he wrote, “There is no life except through direct succession.” Finally, in 1855, in The Archiv, Virchow powerfully concluded, Omnis cellula a cellula (Every cell comes out of a preexisting cell).
It is perhaps impossible to convey the solemnity of the statement, Omnis cellula a cellula, other than to compare it to a book that would be published four years later, in 1859, by Charles Darwin—On the Origin of Species. When we greet a stranger, we ask, “Where are you from?” It is natural to ask about someone’s origin and upbringing. The most insightful and ingenious researchers have always been able to delve more profoundly than their brethren, to see further and connect the philosophical dots. Virchow, like Darwin, combined imagination and years of scientific struggles to formulate an overarching idea about our beginnings. Each of us is a conglomeration of cells, dividing again and again and again, achieving specialization and unique functionality. Embryologists, in time, would discover that every animal starts its journey as a single cell, multiplying its number of cells through division; the only exception is at the spark of life, when two cells (the egg and the sperm) combine to form one.
The original cells in the morula (from the Latin word for mulberry) are “indeterminate,” able to become any cell in any organ of the body. These are the original stem cells, almost supernatural in their ability to respond and adapt and transfigure. All our lives our cells are responding and obeying the chemical messages from surrounding cells, committing themselves along a particular cell line, thereby forming an advanced cellular neighborhood and eventually functioning tissues and organs. Gone awry, the abnormal cell loses function, and worse, achieves a diabolical characteristic that not only impedes normal cellular and organ function, but hastens death.
Virchow and his successors fathomed the significance of the cellular basis of life—forever destroying the ancient, mystical speculations about vital spirits, humors, and life forces. The need to restore “an ill-understood balance that had become jangled”19 was repudiated with the understanding of disease as a set of “disordered biochemical phenomena”20 that would, in the future, be addressed by therapeutic interventions aimed at the locus of dysfunction.
Miasma, bad air, unbalanced humors, and astrology were swept away by anyone willing to pay attention. Virchow’s magnum opus was his textbook Cellular Pathology, published in 1858, which demanded a new approach in the “advancement of medical science.” This became the playbook for the next century’s medical research accomplishments. William H. Welch, the “Dean of American Medicine” at the founding of Johns Hopkins University, ranks Virchow’s book alongside the works of Vesalius, Harvey, and Morgagni as “the greatest advance which scientific medicine had made since its beginning.”21
Perhaps Virchow did achieve “no less than a universal knowledge of nature from the God-head down to the stone” that he hoped for as a young man. Sherwin Nuland describes him as “Hippocrates with a microscope.” Together with his Teutonic microscopy colleagues (who would use advanced stains like H&E in the 1870s), Virchow established Germany as the medical mecca in the mid- to late–19th century, and the surgeons in Germany and Austria (Langenbeck and Billroth in primacy) shared the limelight as the epicenter of learning.
It has been claimed earlier in this book that for the first 295 generations of modern man’s existence, an afflicted individual was always better off “going it alone” rather than seeking care from a healer or physician. It is only in the last five generations that a wise patient could expect improvement in their lot by seeking medical attention. Rudolf Virchow, as much as any physician-scientist, deserves the credit for turning our attention to the cell as the foundational building block of life, the currency used by the universe to absorb nutrients, exchange energy, build tissue, respond to stress, store information, serve as communication centers, and to form gametes (ova and sperm) to create another life. Virchow’s record is not unblemished—he denied Darwinism and the germ theory his entire life—but his concept of the cellular basis of disease, the Archive, his two thousand authored manuscripts, and his long list of apprentices, enshrined him in the Pantheon of medicine, and more importantly, ushered in a metamorphosis in medicine that cracked open the vault of the truths of the inner workings of all cells, tissues, and organs.
In the space of a century, physicians had awakened to the notion of the organ basis of disease, which rapidly advanced to the cellular basis of disease. This, of course, would further evolve into the genetic basis of disease once the understanding of deoxyribonucleic acid (DNA) was realized. Understanding the cell as the building block of life unfettered physicians from millennia of superstition, and the rise of industrial chemistry would soon result in chemotherapeutics that were efficacious. In the late 19th century, surgeons transmuted from bleeders and abscess drainers into diagnosticians—coconspirators with pathologists in their quest to identify and treat disease. Surgeons had long attempted to shake off the association with barbers, but their search for significance would be achieved not by heroic acts and displays of dexterity, but via a scientific reorientation. It is no accident that the greatest surgeons were cultivated in centers where pathology was most warmly embraced; surgeons have never been “wellness” professionals, but are instead mercenaries called upon in the face of catastrophe and therefore, by necessity, must be nurtured in environments where disease and traumatic injuries are investigated and explained.
The contributions of a group of surgeons in Europe, and for the first time, America, would finally raise the stature of surgeons from the lowliest to the recognized. These pioneering surgeons conducted investigations, used experimental tools (like microscopes), altered techniques, reviewed their outcomes, and, for the first time, started to improve the lot of their fellow man. Amazingly, in the late 19th century, surgeons did the unthinkable. Instead of just operating on people in extremis, at the point of death, surgeons began the practice of elective surgery, paving the way for our modern world, where patients seek operations for conditions that not only are non–life threatening, or even causing great pain, but for conditions that are inconvenient, annoying, or even just aesthetically unpleasing.