by Bill Hayes
Every biographer summing up Ehrlich’s life mentions his passion for detective fiction. Martha Marquardt, for instance, revealed that Saturdays at the lab were made sacred by the arrival of the latest issue of the doctor’s favorite crime magazine, with, as she described with an implied tsk-tsk, “its cover showing the most lurid pictures of murder.” This weekly serial magazine was probably akin to the American “pulps” that became popular in the early 1900s, such gritty treats as Detective Story Magazine, Black Mask, and The Shadow. Though they were called pulps because of the cheap, wood-specked paper they were printed on, the stories were sensational and soaked in intrigue. Paul would devour the new issue that same night, Marquardt reported, and it never failed to distract the doctor from his true-life problems.
Ehrlich was also a huge admirer of Sir Arthur Conan Doyle, a signed portrait of whom held pride of place on the wall of his study. He owned copies of many of his books, several of which had been personally inscribed by the Scottish physician-turned-author. As to the when and wherefore of the first “meeting” between Ehrlich and Sir Arthur’s most esteemed creation, the inimitable Sherlock Holmes, my sources do not say. But if one considers that the first Holmes novel, A Study in Scarlet (1887), was published just a few months before Ehrlich began his convalescence, it’s not too great a stretch to imagine he brought along a copy of the new whodunit.
“Voilà, hemoglobin.”
While A Study in Scarlet is most memorable for presenting the first meeting between Holmes and Dr. John Watson, I take particular notice of what immediately follows this historic handshake. Holmes, in his own estimation, has just made an utterly brilliant discovery about bloodstains. He seizes Watson by the coat sleeve and tugs him into the spacious laboratory to demonstrate said brilliance. Given that arrests were often made long after the commission of a violent act, the detective explains, it had theretofore been difficult for the London police to prove that incriminating stains found on a suspect’s clothing were blood rather than, say, fruit or rust stains. But no longer, as Holmes shows. He pricks his own finger with a needle, draws some blood into a pipette, and stirs a drop into a liter of water. Of course, all evidence of scarlet disappears. But wait. Holmes, re-creating an actual forensics innovation of the time, crushes a few white crystals into the water, followed by several drops of a transparent fluid. In an instant, the liquid takes on a dull mahogany color, and a brownish precipitate collects at the bottom. Voilà, hemoglobin. Holmes is so delighted with himself he’d be patting himself on the back were his hands not occupied with the experiment.
When Dr. Ehrlich did read A Study in Scarlet, I can’t help but wonder if he noted the characteristics he and Sherlock Holmes shared: how both men’s hands, to borrow Watson’s words, were “invariably blotted with ink and stained with chemicals”; how, although they both brought a broad background in the sciences to whatever subject was at hand, each possessed an enthusiastic “knowledge of sensational literature”; and how both men incessantly smoked strong tobacco (no, not even TB could make Ehrlich give up cigars). There may have even been aspects of this character’s life that Ehrlich dreamed of having for himself—the unquestioned autonomy, for instance; the instant respect; and, perhaps above all, that gloriously spacious laboratory.
Brushing aside all speculation now, the fact is, when the Ehrlichs returned to Berlin in the spring of 1889, Paul was a new man—free of TB, hale and hearty, raring to jump back into full-time work. Just one snag: Nobody was hiring. Though far from his dream scenario, he made the best of the situation. With the financial backing of his father-in-law, the thirty-five-year-old opened his own research laboratory, which may sound more glamorous than it was. In truth, it was a rented apartment, close to where he and his family lived. And his staff rounded out to a whopping one, a valet named Fritz, although Paul’s nephews, Felix and Georg, did pitch in now and then. Picking up where he’d left off the year before, Ehrlich resumed his experiments with vital staining and began creating new histological dyes. He christened Stieglitz blue and Lutzow blue for nearby streets. A more informal term—exploders—arose to describe a common mishap: the bursting of the dye-filled glass flasks that were heated on the apartment’s kitchen stove, leaving indigo spattered about the room.
Elsewhere in the small apartment, Ehrlich launched into what was for him a new line of research, work that was related to a larger “hot theory” being addressed by scientists in Berlin, as elsewhere: that all infectious diseases were caused by toxins, a by-product of foreign microorganisms. Scientists had just concluded that this was the case in diphtheria, for instance; the diphtheria bacterium secreted a toxic substance that attacked the walls of the throat, producing the blockage that left its victims, mostly children, choking to death. Soon after, it was found that a toxin was also the culprit in tetanus. Scientists then cast a suspicious eye on TB (although, eventually, no toxin was implicated). Ehrlich, a man who “approached research like a detective on a trail,” as the distinguished American hematologist Maxwell Wintrobe wrote in 1980, began focusing on one small aspect of the whole. He mounted his own quantitative study of a toxin, but rather than something infectious, Ehrlich chose something addictive: cocaine.
At the time, cocaine was legal and readily available, whether in pure form from a pharmacist or, as was the case in Anytown, USA, at the corner drugstore as the extra little kick in a glass of Coca-Cola. Coincidentally, the second Sherlock Holmes story, The Sign of Four (1890), had just been published, and it opened with Holmes casually injecting himself with a syringe of cocaine, the influence of which, he confessed to Watson, he found “transcendentally stimulating and clarifying.” Its popularity notwithstanding, Ehrlich knew that at certain levels cocaine had toxic effects. But what levels caused what effects? For answers, Ehrlich enlisted mice as his guinea pigs. Rather than injecting the cocaine into their bloodstreams, he instead found it easier and safer to feed it to them. He soaked biscuits with varied but precise quantities of a cocaine solution. Satisfied with this methodology, Ehrlich shifted to a series of experiments using a much deadlier plant derivative, the toxin ricin. Derived from castor plant beans, ricin is more potent than cobra venom, even in minuscule amounts. Today it is regarded as one of the most dangerous weapons of bioterrorism.
Although Ehrlich would end up with a lot of dead mice, he eventually produced survivors that were immune to not just normally lethal amounts of ricin but also doses hundreds of times stronger. Within the bloodstream of these supermice, Ehrlich had triggered circulating “antitoxins” (a type of antibody) that would “paralyze” the poison the next time the mice ingested it. In short, they’d been vaccinated. With this, Ehrlich was not, however, introducing into the world a new concept. A hundred years earlier one of his scientific heroes, the British physician Edward Jenner, had demonstrated an effective but far cruder instance of induced immunity. He’d found that a human being deliberately exposed to a mild form of smallpox, by way of scrapings from sores, would survive exposure to the deadly form of the disease. Although the how and why were unclear, Jenner had proven, figuratively speaking, that an umbrella against drizzle could be as effective in a downpour. In turning to this puzzle a century later, Ehrlich brought to the table his own specialty: great scientific rigor. With his ricin experiments, he developed a scrupulous methodology, juggling multiple factors. As a result, he knew exactly how much of the toxin was required to elicit immunity, according to a specific dosing schedule over a certain number of days. Likewise, he knew what amounts were too little or more than necessary. When his supermice had offspring, Ehrlich discovered something else of significance. The antitoxins were being passed on by the mother, from placenta to fetus as well as through suckling—textbook examples of passive immunization, in which an individual receives antibodies from another. (In active immunization, by contrast, protective antibodies are generated by one’s own immune system.)
Ehrlich’s methods and precision caught the attention of his peers, one of whom, fellow Berliner Dr. Emil von Behr
ing, had just made his own startling discovery regarding passive immunity. In experiments completed in 1890, Behring found that if he removed the serum (the plasma without the blood cells and clotting elements) from an animal that had been successfully immunized against diphtheria, and then injected it into a second animal, that animal would also be immune. Serum from the injected animal would, in turn, protect other animals. Taking the next step, however—creating a diphtheria antitoxin to protect human beings—had proved troublesome. Behring wisely enlisted Ehrlich’s help in developing a safe, effective protocol. Ultimately, full-scale production of the lifesaving diphtheria treatment began in November 1894.
Paul Ehrlich in his laboratory
From there, a five-year jump in time finds a world-recognized Paul Ehrlich as the head of his own institute, the newly established Royal Institute of Experimental Therapy, located in Frankfurt—a long distance, both geographically and professionally, from his cramped quarters in Berlin. The institute had been designed to Ehrlich’s every specification, with multiple laboratories, a library, and ample space for a top-notch staff plus countless lab animals, all housed within a grand four-story building. Ehrlich oversaw a broad range of work whose scope was comparable, for its time, to, say, the United States’ National Institutes of Health combined with the Food and Drug Administration. While its opening ceremony in early November 1899 was a splendid public affair, attended by scientists, journalists, politicians, and citizenry, for Dr. Ehrlich personally a much more prestigious, albeit quieter, event would take place four months later.
It is March 22, 1900, and the forty-six-year-old Paul Ehrlich stands before the Royal Society of London—the exclusive scientific association that counts Antoni van Leeuwenhoek and Sir Isaac Newton among its past members. When he speaks of the great privilege it is to be here, this is no mere nicety. He has been invited to this first gathering of the new century to deliver the keynote address, a lecture titled “On Immunity with Special Reference to Cell Life.” He does not disappoint. In this now-legendary speech Dr. Ehrlich elaborates for the first time his “side-chain theory” of immunity, which provides a full accounting of the blood’s ability to protect the body from foreign invaders. Drawing upon the work of peers as well as his experience with ricin and diphtheria, Ehrlich explains that blood cells have on their surfaces ready-made receptor molecules, or “side chains,” that link or bind chemically with certain invading toxin molecules. (He had borrowed the term side chain from organic chemistry; it was widely believed that side chains were, like docking ports, the means by which cells took in nourishment from free-floating food particles.) Long story short, this binding neutralizes the toxins. It also triggers production of excess side chains, which are released into the blood as circulating antitoxins to fight the same toxin in the future.
Medical historians today distill Ehrlich’s presentation to three main points, two of which were correct and one that was wrong but forgivable. He was right in theorizing that blood cells have the capacity to form antibodies even before a particular antigen has entered the body. Also right was his conception of these antibodies as, in essence, locks waiting for the right keys; and the related notion that, once a lock was activated, the production of many more antibodies was stimulated. Ehrlich was mistaken, though, in believing that all cells could produce such antibodies; in fact, only B lymphocytes can.
Historians also agree that Ehrlich’s argument was not just sound but very convincing. Adding to the impact of his spoken word was a series of provocative drawings. Now, it should be noted that the use of visual aids in a lecture to the Royal Society was not at all unusual, but his were unique for being of imagined constructs, renderings of the theoretical goings-on in the blood. Even though the best microscopes of the day did not allow Paul Ehrlich to see this activity, in his mind’s eye the images were clear. And were now on display. A sequence unfolded: First a standard cell was shown—a light-colored, spongy moon erupting with what looked like sweat beads off the brow of a comic-strip character. These were Ehrlich’s side chains, which frankly did not in any way appear chain-like. Next, some of the sweat beads were gripped by toxins, the villainous elements, which were horned and black. Others then broke free—the heroic antitoxins—and, now resembling lithe, silvery minnows, swam off into the blood.
Ehrlich, aware that not everyone in the audience would share his certainty, cautioned that the forms and shapes in his diagrams should be considered as “purely arbitrary.” At best, they were simply an educated guess. Some scientists did not take this caveat to heart, however. In the weeks and months to follow, critics griped that his ridiculous “cartoons” had conveyed more of a conclusion than a possibility. His chief detractor dubbed them a “puerile graphical representation.” If the criticism was meant to elicit a retraction of some sort, it didn’t work. In fact, whenever Ehrlich subsequently spoke about his side-chain theory, he would take the opportunity to illustrate it. Stories abounded of how Dr. Ehrlich, even in casual conversation with colleagues, would scribble out drawings of the minuscule players of his theory on whatever blank surface was available. When no paper was handy, he’d opt for, say, his hostess’s tablecloth, a listener’s shirt cuff, or the sole of his shoe. If necessary, he’d roll back the carpet, then use chalk on the floorboards. And once, over dinner, in a performance I’m sad to have missed, he storyboarded his entire molecular drama on fifty postcards, an indulgent waiter having kept the doctor in steady supply.
Martha Marquardt, who entered his employ in 1902, adored this quality in her boss. “When his mind was entirely filled with a certain idea,” she wrote, he spoke of it with animation and in a great gallop of words. “He perceived the idea as if it had a physical existence,” and he always wanted visitors to see it along with him. To make sure a person was keeping up, Dr. Ehrlich might tap him or her “lightly on the arm or chest with the point of a coloured pencil, with a test tube, a cigar or his thick-rimmed spectacles which he frequently took off and swung about. . . .” Drawing to a finish, “he stood with his head pushed forward a little, his gentle face upraised,” and “looked penetratingly at the other person with his big bright eyes.” Do you see what I see?
Dr. Ehrlich never actually got to view the drama within the blood. But what was to him the most likely scenario involving the most likely suspects can now be clearly photographed with an electron microscope, the same technology used to produce those ugly mug shots of minute insects, with their bulbous compound eyes. The electron microscope, thousands of times stronger than the traditional compound microscope, has also captured images of a tinier but more horrific bug: HIV, the virus that does its damage to the immune system by hijacking helper T cells and forcing them to churn out as many copies of itself as possible, a process that kills the cells. I remember the odd sense of relief I felt upon first seeing the micrograph of HIV on the cover of Time magazine, dated August 12, 1985, one month after I’d moved from Seattle to San Francisco’s Castro district, ground zero of the epidemic. It showed the virus, magnified 135,000 times, attacking a T cell, according to the caption, although the grayish clump looked more like something pulled from a vacuum cleaner bag. There’s the culprit, I thought, staring at the black-and-white photo. Now we just need to annihilate it.
I’ve since seen many similar images, some taken at magnifications three times as powerful. Like the dazzling shots of far-off galaxies taken by the Hubble Space Telescope, the original black-and-white micrographs are often colorized to highlight specific features of the virus. Three-dimensional computer graphics provide even finer details of HIV’s internal and external architecture. I know that these images have been invaluable to scientists in their growing understanding of HIV and in crafting new models for fighting it, but, to me, the greater the complexity of the virus, the bleaker the chances seem of surviving it. The discovery of a cure feels farther off in my lifetime and unlikely in Steve’s.
During rough patches, Steve admits that his life seems to creep forward in three-month intervals, alluding
not to the turn of seasons but to the stretches between his getting blood work, the panoply of tests that measure the virus’s activity and how well his immune system and organs are holding up. The findings provide an assessment of his current drug regimen and help determine the course for the next twelve weeks. Seeing his doctor for the results is always anxiety producing.
Thinking back fourteen years, I don’t remember Steve ever having a slim patient file, although at some distant point in our shared past that must’ve been the case. Now it’s a thick sheaf that’s plopped onto the desktop at the start of each appointment. Once the pleasantries are over, Dr. Hassler opens the file and the three of us huddle over the latest labs, a three-page printout of more than fifty separate tests. The results run down the center of each page in one of two columns: WITHIN RANGE, under which most of Steve’s liver and kidney function results, for example, are listed; and OUTSIDE OF RANGE, where the grimmer numbers, T helper percentages, white cell counts, and the like, are clustered. To make the bad numbers easy to spot, this column is shaded a pale red, a stripe top to bottom. The most recent pages are bound to a thick pile of Steve’s past results, and a quick fanning of the stack creates a crude animation of a red ribbon, many years long.
Across the Bay Bridge and thirty miles from my home, I step from my car and approach IDL, Immunodiagnostic Laboratories. The broad one-story building, here on the outskirts of San Leandro, is situated in a secluded industrial complex. The building proper is faced entirely in black reflective glass, making it impossible for me to glimpse any activity within. What’s more, while a sign confirms that I am definitely at the correct address, I can’t find a front entrance or even the appearance of a door. How apropos, I think; the lab where Steve’s blood is tested is testing me. Stumped about how to get inside, I stare at the building. All I see is myself, looking back.
