Why Did It Take Scientists So Long to Fully Understand Genetics and Mendel’s Laws?
Howard Markel on the Complicated Process of Scientific Inquiry, DNA, and Heredity
“The laws governing inheritance are quite unknown; no one can say why the same peculiarity in different individuals of the same species, and in individuals of different species, is sometimes inherited and sometimes not so; why the child often reverts in certain characters to its grandfather or grandmother or other much more remote ancestor; why a peculiarity is often transmitted from one sex to both sexes or to one sex alone, more commonly but not exclusively to the like sex.”
–Charles Darwin, 1859
*Article continues after advertisement
In the beginning, high on a hill in Brünn, Moravia (now Brno in the Czech Republic), there was an abbey. In 1352, the Augustinian friars built an L-shaped, two-story, stucco and stone monastery topped by a gabled roof of orange clay shingles. The ground floor was arranged around a refectory and a library; directly above was a long, open dormitory for the friars. These rooms overlooked the confluence of the Svitava and Svratka rivers on one side and, on the other, the Gothic, red-bricked Basilica of the Assumption of Our Lady. The powers that were named it the Abbey of St. Thomas, after the apostle who initially doubted the resurrection of Jesus Christ (hence the moniker “Doubting Thomas”).
The abbey’s halls and arcades were overwhelmingly silent except for the chirping of birds, kept on the grounds within mesh-wired cages that the friars built to keep away predators. Wafting about were the smells of boiling hops, yeast, and grains, courtesy of the abbey’s immediate neighbor, the Starobrno brewery, which had quenched the thirst of Brünn’s villagers since 1325. Tucked into a corner of the abbey’s central courtyard was a well-tended garden surrounded by a manicured stretch of grass. There, a monk named Gregor Mendel grew tomatoes and beans and cucumbers. He was proudest of his pea plants, which sprouted in a veritable Punnett square of all shapes, sizes, and colors.
Born in 1822, Johann Mendel (he took the name Gregor upon joining the Augustinian order) hailed from a family of farmers who tended a plot of land near the Moravian–Silesian border. As a boy, Mendel loved gardening and beekeeping. He sailed through the local schools and matriculated into the nearby university in Olemac in 1840. Three years later, in 1843, he was forced to disenroll before taking his degree because money was short and tuition was high.
Determined to continue his studies, Mendel gave up his few earthly possessions and entered monastic life at St. Thomas in 1843. He thanked God in his nightly prayers for no longer having to worry about eking out a living or repaying his family’s debts. His cot was comfortable and the meals bountiful. And because the abbey was the intellectual hub of Brünn, in 1851 Mendel convinced the abbot to find the discretionary funds to cover the expense of sending him to the University of Vienna. There, Mendel excelled in physics, agriculture, biology, and research on the hereditary traits of plants and sheep. Intellectually gifted, Mendel was less the doubting St. Thomas than he was a finder of things and ideas, like St. Anthony.
When Friar Gregor returned to Brünn in 1853, the abbot assigned him the task of teaching physics in the local high school, even though he twice failed the oral examinations to become a certified teacher. He much preferred tending his garden to his parish duties. On this tiny patch of land, Mendel cultivated the modern study of heredity. Each day, he carefully recorded his observations of seven variations in the successive, self-fertilizing generations of his pea plants: height, pod shape and color, seed shape and color, and flower position and color.
Soon after Mendel began cross-breeding the tall plants with the “dwarf,” or short, plants, he noted that all plants in the successive generation were tall. He thus called the characteristic of “tallness” a dominant trait and the trait of “dwarfism” recessive. In the next generation, bred from the hybrid plants, he observed both traits, tallness and dwarfism, expressed in a three-to-one, dominant-to-recessive ratio. Mendel found fixed ratios in the pea plants’ other dominant and recessive traits as well. Eventually, he developed mathematical formulae to predict how these traits would express themselves in successive generations and fertilization. He believed these phenomena to be caused by “invisible factors”—what we now know as genes.
Mendel was less the doubting St. Thomas than he was a finder of things and ideas, like St. Anthony.
The friar presented his studies at two consecutive meetings of the Brünn Natural Science Society on the evenings of February 8th and March 8, 1865. Today, it might seem odd to attend a scientific seminar and find a monk dressed in his ankle-length black woolen habit with a long, black pointed hood, or capuche, adorning his back. But the Brünn Natural Science Society was well attended by friars of the abbey, intellectual townsmen, and even curious farmers from the adjoining countryside. With only a chalkboard to present his complex formulae and in a voice almost whispery from years of quiet solitude, Mendel simultaneously impressed and bewildered the 40-odd members in the room.
Later than year, Mendel published his lectures in the society’s proceedings. Sadly, Verhandlungen des naturforschenden Vereines in Brünn (Transactions of the Natural Science Society of Brünn) did not enjoy a wide circulation, and Mendel’s discoveries failed to set the world afire. Armchair historians have often cited the obscure venue where he published his work as the cause of this delayed recognition, but it was more complicated than that. Mendel’s description of heredity as occurring in discrete, predictable units ran counter to his era’s explanations of the workings of the body and reproduction. The conventional wisdom of the day held that the balance of four bodily humors (blood, phlegm, yellow bile, and black bile) controlled the functioning of our organs and even the personalities of the children one produced.
This centuries-old theory was just plain wrong, but disproving it required several more decades of scientific inquiry. Further, the mathematics Mendel used to interpret his data was foreign to the ways biologists and natural historians thought about science, many of whom were still struggling to comprehend, if not accept, Darwinian theory. The natural historians of Mendel’s day were far more comfortable collecting, naming, and classifying different species based upon morphological characteristics.
Alas, Mendel spent the last 17 years of his life as the abbot of St. Thomas and became embroiled in a dispute with the imperial Austro-Hungarian bureaucracy over the abbey’s tax bills. He died at 62 of chronic kidney disease, in 1884. Sixteen more years elapsed before, in 1900, a Dutch botanist (Hugo de Vries), an Austrian agronomist (Erich von Schermack–Seysenegg), a German botanist (Karl Correns), and an American agricultural economist (William Jasper Spillman) independently applied some intrepid librarianship, ferreted out Mendel’s paper from the dusty stacks, and verified his results. Only the most obsessive recall these four scientists today because they so graciously (and honestly) gave the credit of primacy to Gregor Mendel. In recent years, a small band of post hoc detractors have suggested that Mendel fudged his data, because the mathematical ratios reported in his paper were too perfect to be statistically possible. Many more biologists and biostatisticians, however, have fervently come to Mendel’s defense. Most historians now agree that Mendel was certainly correct and probably honest in his reporting.
The rediscovery of Mendel’s “laws” governing the transmission of simple recessive and dominant traits became the foundation of modern genetics. He has since earned his posthumous immortality as the father—or at least the friar—of what came to be known as classical or Mendelian genetics. The major problem of this system is that most inherited traits are not simple and arise from the interaction of several genes, which can also change their expression under environmental, social, and other influences.
*
During the autumn of 1868, three years after Mendel published his paper, Johannes Friedrich Miescher was wringing out pus from bandages he had just collected from a surgical ward in Tübingen. A newly-minted Swiss physician (MD, Basel, 1868), Miescher came from good stock and station. His father, Johann F. Miescher, was a professor of physiology at the University of Basel; his uncle, Wilhelm His, a professor of anatomy at Basel, revolutionized the fields of neurobiology, embryology, and microanatomy.
Since childhood, Miescher had contended with significant hearing loss, the result of an ear infection that smoldered into his mastoid sinus. This presented a problem for him as he segued from the classroom into the hospital and clinic, making the verbal give-and-take between physician and patient difficult. His father and uncle agreed that it might do him some good to take time off before embarking upon a clinical practice. They used their connections to arrange a plum research position for him in the laboratory of Professor Felix Hoppe-Seyler at the University of Tübingen. Hoppe-Seyler was the founder of modern biochemistry. Among his many discoveries was the oxygen-carrying function of red blood cells—the role played by the protein hemoglobin and its key ingredient, iron.
Hoppe-Seyler’s laboratory was situated in what was once the basement vault of Hohentübingen Castle. It consisted of a suite of narrow rooms with deep-set, arched windows overlooking the river Neckar and the Ammar Valley. Miescher fell in love with the place and, under Hoppe-Seyler’s guidance, studied the contents of neutrophils and leukocytes, or white blood cells, which course through the bloodstream in search of foreign invaders and attempt to ward off infection. He chose white blood cells because they are not embedded in tissue and are thus more easily isolated and purified; also, they have especially large nuclei, which serve as the cell’s command center, that can be visualized when placed under the magnifying objective of a light microscope.
As it turned out, there were few better ways to collect white blood cells than from greenish-gray, pus-saturated bandages that had wrapped surgical patients. Surgeons of the mid-19th century espoused a now discarded concept known as “laudable pus.” Deeming pus to be the by-product of healing after a gruesome operation, they considered that the more pus a wound produced—often the result of the surgeon’s dirty knife and hands—the more likely it was to heal. In most cases, we now know, the overproduction of pus translates into an ongoing postoperative infection. The all too common result of “laudable pus” was that the infection spread through the bloodstream and sent the patient into the death spiral known as sepsis.
It took a little more than another half-century before anyone figured out what DNA actually did.
As often happens in scientific inquiry, Miescher benefited from a temporal coincidence of technology created by another investigator. His benefactor was Dr. Viktor von Bruns, director of the University of Tübingen surgical clinic, who had just created a woven, highly absorbent cotton material he called “woolen cotton.” We know it today as gauze. Postoperative infections aside, this new, sponge-like bandage was instrumental in Miescher’s daily collection of pus.
In time, Miescher learned how to better free the delicate white blood cells from the liquid portion of the pus collected in these bandages without damaging or destroying them entirely—no easy task. Fortunately, he had what surgeons call “good hands” and developed a series of chemical techniques, precipitating out a heretofore-undescribed substance rich in phosphorus and acid. Miescher determined that this substance was found only in a cell’s nucleus and named the new entity nuclein. Today, we call Miescher’s substance deoxyribonucleic acid, or DNA. In casual conversation, people often mistakenly state that Watson and Crick discovered DNA, when in fact they discovered the molecular structure of what Friedrich Miescher chemically identified 84 years earlier in 1869.
Miescher left Tübingen in 1871 for Leipzig, where he worked under the renowned physiologist Carl Ludwig. During this year, he prepared a paper on his studies of nuclein and, after a scrupulous review of his highly reproducible data, Dr. Hoppe-Seyler agreed to publish his findings in an 1871 issue of the prestigious journal he edited, Medicinisch–chemische Untersuchungen (Studies in Medicinal Chemistry). In an editorial accompanying Miescher’s paper, Hoppe-Seyler added his powerful endorsement of nuclein’s scientific novelty.
The following year, Miescher returned to his hometown of Basel to serve his Habilitation, a postdoctoral lectureship and entry-level academic position for young physicians in Germany, Austria, and Switzerland during the 19th century. In 1872, at age 28, he was offered the position of chair and professor of physiology at the University of Basel. Because both his father and uncle had held prestigious professorships there, jealous colleagues made unfounded complaints of nepotism. Miescher proved them wrong and thrived in the role of scientific investigator.
The University of Basel was situated on the banks of the river Rhine. Its location allowed for another wonderful coincidence. Salmon fishing was a major industry in Basel. Salmon sperm cells, too, were easily isolated and purified using the chemical techniques of Miescher’s era. They also happen to contain especially large nuclei and, hence, more nuclein to extract and study. Thus, Miescher enjoyed fishing for an unending river of salmon gonads. In the laboratory, he determined that nuclein consisted of carbon, phosphorus, hydrogen, oxygen, and nitrogen. Miescher’s earlier attempts at studying nuclein, incidentally, were often contaminated by stray proteins and their constituent, sulfur.
In 1874, Miescher reported many similarities (and some subtle differences) of nuclein across different vertebrate species. At one point in his paper, Miescher hovered near the scientific jackpot with a somewhat tepid sentence: “if one… wants to assume that a single substance… is the specific cause of fertilization, then one should undoubtedly first and foremost consider nuclein.” After a great deal of hemming and hawing, however, he ultimately could not fathom how so complex a process as reproduction could be guided by a simple chemical entity with such “limited diversity.” A few sentences later, he concluded, “there is no specific molecule that could explain fertilization.”
Like Gregor Mendel, poor Miescher sank into the quagmire of administrative squabbles at the expense of time better spent in contemplative thought. He died of tuberculosis, in 1895, at the age of 51. An institute for biomedical research is named for him at the University of Basel. Outside of his hometown, however, few recall his name and work. It took a little more than another half-century before anyone figured out what DNA actually did. Before that happened, unfortunately, the academy’s understanding of heredity careened off the rails.
__________________________________
Excerpted from The Secret of Life: Rosalind Franklin, James Watson, Francis Crick, and the Discovery of DNA’s Double Helix. Copyright © 2021 by Howard Markel. Used with permission of the publisher, W. W. Norton & Company, Inc. All rights reserved.
