A Fetish for Examining Objectionable Fluids
Miescher hadn’t originally planned to join this movement to demystify life. As a young man he had trained to practice the family trade, medicine, in his native Switzerland. But a boyhood typhoid infection had left him hard of hearing and unable to use a stethoscope or hear an invalid’s bedside bellyaching. Miescher’s father, a prominent gynecologist, suggested a career in research instead. So in 1868 the young Miescher moved into a lab run by the biochemist Felix Hoppe-Seyler, in Tübingen, Germany. Though headquartered in an impressive medieval castle, Hoppe-Seyler’s lab occupied the royal laundry room in the basement; he found Miescher space next door, in the old kitchen.
Hoppe-Seyler wanted to catalog the chemicals present in human blood cells. He had already investigated red blood cells, so he assigned white ones to Miescher — a fortuitous decision for his new assistant, since white blood cells (unlike red ones) contain a tiny internal capsule called a nucleus. At the time, most scientists ignored the nucleus — it had no known function — and quite reasonably concentrated on the cytoplasm instead, the slurry that makes up most of a cell’s volume. But the chance to analyze something unknown appealed to Miescher.
To study the nucleus, Miescher needed a steady supply of white blood cells, so he approached a local hospital. According to legend, the hospital catered to veterans who’d endured gruesome battlefield amputations and other mishaps. Regardless, the clinic did house many chronic patients, and each day a hospital orderly collected pus-soaked bandages and delivered the yellowed rags to Miescher. The pus often degraded into slime in the open air, and Miescher had to smell each suppurated on cloth and throw out the putrid ones (most of them). But the remaining “fresh” pus was swimming with white blood cells.
Eager to impress — and, in truth, doubtful of his own talents — Miescher threw himself into studying the nucleus, as if sheer labor would make up for any shortcomings. A colleague later described him as “driven by a demon,” and Miescher exposed himself daily to all manner of chemicals in his work. But without this focus, he probably wouldn’t have discovered what he did, since the key substance inside the nucleus proved elusive. Miescher first washed his pus in warm alcohol, then acid extract from a pig’s stomach, to dissolve away the cell membranes. This allowed him to isolate a gray paste. Assuming it was protein, he ran tests to identify it. But the paste resisted protein digestion and, unlike any known protein, wouldn’t dissolve in salt water, boiling vinegar, or dilute hydrochloric acid. So he tried elementary analysis, charring it until it decomposed. He got the expected elements, carbon, hydrogen, oxygen, and nitrogen, but also discovered 3 percent phosphorus, an element proteins lack. Convinced he’d found something unique, he named the substance “nuclein” — what later scientists called deoxyribonucleic acid, or DNA.
Miescher polished off the work in a year, and in autumn 1869 stopped by the royal laundry to show Hoppe-Seyler. Far from rejoicing, the older scientist screwed up his brow and expressed his doubts that the nucleus contained any sort of special, nonproteinaceous substance. Miescher had made a mistake, surely. Miescher protested, but Hoppe- Seyler insisted on repeating the young man’s experiments — step by step, bandage by bandage — before allowing him to publish. Hoppe-Seyler’s condescension couldn’t have helped Miescher’s confidence (he never worked so quickly again). And even after two years of labor vindicated Miescher, Hoppe-Seyler insisted on writing a patronizing editorial to accompany Miescher’s paper, in which he backhandedly praised Miescher for “enhanc[ing] our understanding… of pus.” Nevertheless Miescher did get credit, in 1871, for discovering DNA.
Some parallel discoveries quickly illuminated more about Miescher’s molecule. Most important, a German protégé of Hoppe-Seyler’s determined that nuclein contained multiple types of smaller constituent molecules. These included phosphates and sugars (the eponymous “deoxyribose” sugars), as well as four ringed chemicals now called nucleic “bases” — adenine, cytosine, guanine, and thymine. Still, no one knew how these parts fit together, and this jumble made DNA seem strangely heterogeneous and incomprehensible.
(Scientists now know how all these parts contribute to DNA. The molecule forms a double helix, which looks like a ladder twisted into a corkscrew. The supports of the ladder are strands made of alternating phosphates and sugars. The ladder’s rungs — the most important part— are each made of two nucleic bases, and these bases pair up in specific ways: adenine, A, always bonds with thymine, T; cytosine, C, always bonds with guanine, G. [To remember this, notice that the curvaceous letters C and G pair-bond, as do angular A and T.])
Meanwhile DNA’s reputation was bolstered by other discoveries. Scientists in the later 1800s determined that whenever cells divide in two, they carefully divvy up their chromosomes. This hinted that chromosomes were important for something, because otherwise cells wouldn’t bother. Another group of scientists determined that chromosomes are passed whole and intact from parent to child. Yet another German chemist then discovered that chromosomes were mostly made up of none other than DNA. From this constellation of findings — it took a little imagination to sketch in the lines and see a bigger picture — a small number of scientists realized that DNA might play a direct role in heredity. Nuclein was intriguing people.
Miescher lucked out, frankly, when nuclein became a respectable object of inquiry; his career had stalled otherwise. After his stint in Tübingen, he moved home to Basel, but his new institute refused him his own lab — he got one corner in a common room and had to carry out chemical analyses in an old hallway. (The castle kitchen was looking pretty good suddenly.) His new job also required teaching. Miescher had an aloof, even frosty demeanor — he was someone never at ease around people — and although he labored over lectures, he proved a pedagogical disaster: students remember him as “insecure, restless… myopic… difficult to understand, [and] fidgety.” We like to think of scientific heroes as electric personalities, but Miescher lacked even rudimentary charisma.
Given his atrocious teaching, which further eroded his self-esteem, Miescher rededicated himself to research. Upholding what one observer called his “fetish of examining objectionable fluids,” Miescher transferred his DNA allegiance from pus to semen. The sperm in semen were basically nuclein-tipped missiles and provided loads of DNA without much extraneous cytoplasm. Miescher also had a convenient source of sperm in the hordes of salmon that clogged the river Rhine near his university every autumn and winter. During spawning season, salmon testes grow like tumors, swelling twenty times larger than normal and often topping a pound each. To collect salmon, Miescher could practically dangle a fishing line from his office window, and by squeezing their “ripe” testes through cheesecloth, he isolated millions of bewildered little swimmers. The downside was that salmon sperm deteriorates at anything close to comfortable temperatures. So Miescher had to arrive at his bench in the chilly early hours before dawn, prop the windows open, and drop the temperature to around 35°F before working. And because of a stingy budget, when his laboratory glassware broke, he sometimes had to pilfer his ever-loving wife’s fine china to finish experiments.
From this work, as well as his colleagues’ work with other cells, Miescher concluded that all cell nuclei contain DNA. In fact he proposed redefining cell nuclei — which come in a variety of sizes and shapes — strictly as containers for DNA. Though he wasn’t greedy about his reputation, this might have been a last stab at glory for Miescher. DNA might still have turned out to be relatively unimportant, and in that case, he would have at least figured out what the mysterious nucleus did. But it wasn’t to be. Though we now know Miescher was largely right in defining the nucleus, other scientists balked at his admittedly premature suggestion; there just wasn’t enough proof. And even if they bought that, they wouldn’t grant Miescher’s next, more self-serving claim: that DNA influenced heredity. It didn’t help that Miescher had no idea how DNA did so. Like many scientists then, he doubted that sperm injected anything into eggs, partly because he assumed (echoes of the homunculus here) that eggs already contained the full complement of parts needed for life. Rather, he imagined that sperm nuclein acted as a sort of chemical defibrillator and jump-started eggs. Unfortunately Miescher had little time to explore or defend such ideas. He still had to lecture, and the Swiss government piled “thankless and tedious” tasks onto him, like preparing reports on nutrition in prisons and elementary schools. The years of working through Swiss winters with the windows open also did a number on his health, and he contracted tuberculosis. He ended up giving up DNA work altogether.
Meanwhile other scientists’ doubts about DNA began to solidify, in their minds, into hard opposition. Most damning, scientists discovered that there was more to chromosomes than
phosphate-sugar backbones and A‑C‑G‑T bases. Chromosomes also contained protein nuggets, which seemed more likely candidates to explain chemical heredity. That’s because proteins were composed of twenty different subunits (called amino acids). Each of these subunits could serve as one “letter” for writing chemical instructions, and there seemed to be enough variety among these letters to explain the dazzling diversity of life itself. The A, C, G, and T of DNA seemed dull and simplistic in comparison, a four-letter pidgin alphabet with limited expressive power. As a result, most scientists decided that DNA stored phosphorus for cells, nothing more.
Sadly, even Miescher came to doubt that DNA contained enough alphabetical variety. He too began tinkering with protein inheritance, and developed a theory where proteins encoded information by sticking out molecular arms and branches at different angles — a kind of chemical semaphore. It still wasn’t clear how sperm passed this information to eggs, though, and Miescher’s confusion deepened. He turned back to DNA late in life and argued that it might assist with heredity still. But progress proved slow, partly because he had to spend more and more time in tuberculosis sanitariums in the Alps. Before he got to the bottom of anything, he contracted pneumonia in 1895, and succumbed soon after.