Brilliance shone from the heartland to NYC only to fade with lost opportunities for all
From the farm to the big city
At the turn of the 20th century, a farm boy enrolled at the University of Kansas to study engineering, hoping to fortify a natural talent honed by years of maintaining and fixing machinery on the family farm. But Walter Stanborough Sutton’s engineering career took a detour when his younger brother died of typhus in 1897, and Walter switched to biology and medicine. He graduated with a bachelor and master’s degree in 1901 where his thesis focused on spermatogenesis (formation of sperm cells) in the lubber grasshopper (Brachystola magna), native to the American Midwest. Walter continued using this insect as his model organism when he went to Columbia University in New York City to study zoology with Dr. E. B. Wilson. His next two papers published in 1902 and 1903 were landmark studies that established chromosomes as the physical basis for Mendel’s mathematically derived heritable factors. This is his story...
In part 1 of this series we talked about Mendel publishing his groundbreaking theory on the heritability of traits by independently segregating and assorting factors. Mendel’s paper was presented in 1865 and was immediately ignored and forgotten until it was re-discovered in 1900. This was in stark contrast to part 2 where we showed that when Darwin published his theory of evolution by variation and natural selection in 1859, his social standing and network of highly-placed scientific friends ensured an immediate and wide, if not always friendly, reception. One of the weaknesses of Darwin’s theory, and a constant target of criticism that he always regretted, was the lack of a mechanistic explanation for how evolution could occur. Mendel’s paper would have immediately rectified this gap in Darwin’s theory. But Mendel’s paper, in turn, would also have run into its own questions – what is the cellular basis of his heritable factors? And this is what Sutton specifically provided in his two papers.
Where was science at the time when Sutton put his stamp on Mendelian genetics?
Unveiling the cell and the chromosome
Well, biologists had been aware of cells since the invention of the microscope in the mid-seventeenth century by Anton van Leeuwenhoek of the Netherlands and Robert Hooke of England. Hooke published his book Micrographia in 1665 and coined the term “cell” to describe the units from which plants were built. There things stagnated for almost two hundred years until significant improvements in the microscope enabled a deeper look into the contents of the cell. Polish neurologist and embryologist, Robert Remak, was the first to propose in 1855 that cells arose from other cells - thus establishing one of the foundations of cell theory along with Theodor Schwann. Cell theory was kind of like 19th century atomic theory, but for biology; it proposed that all living things are composed of one or more cells, that the cell is the basic unit of life, and that cells arise from other cells. Remak’s role in this discovery was co-opted by Rudolf Virchow, whose name unfortunately is more commonly associated with cell theory today.
The nucleus was discovered and described in the early nineteenth century by Austrian Franz Andreas Bauer and Robert Brown from Scotland, but little was known about its function. In 1842 Swiss botanist Karl Wilhelm von Nageli described thread-like structures within the cell
that later scientists would call chromosomes. But Nageli did not quite describe chromosomes correctly and did not understand their function or role in cells, despite corresponding extensively with Mendel. Furthermore, Nageli failed to cite the monk in his own book on his theory of the mechanics of evolution, published in 1884.
In 1882 German biologist Walther Flemming published an important monograph called Cytoplasm, Nucleus and Cell Division (Zellsubstanz, Kern und Zelltheilung). This book documented the first use of the recently synthesized aniline dyes to visualize cell structures – in this case the threadlike structures he called chromatin for their ability to absorb dyes (I mentioned these dyes in an earlier post about antimalarial drugs).
Flemming was interested in cell division, a process for which he coined the term mitosis (Greek mitos = thread). His beautifully detailed observations of cell division (see image to left) led to his discovery that cell nuclei arose from precursor nuclei, thus building on the cell theory concept that cells arose from other cells.
More important to our story, Flemming deduced from his careful microscopic observations that these stained threads (not yet called chromosomes) split along their length during mitosis and he also hypothesized correctly that they were partitioned into each of two daughter cells. Flemming had described the specific cellular process underlying Mendel’s theory of genetics, which in turn provided the conceptual mechanics for Darwin’s theory of evolution. Unfortunately, Mendel’s work was already forgotten, so Flemming did not recognize the broader implications of his work.
Tying the chromosome to Mendel's Laws
It was not until 1900, after Correns and Devries independently uncovered Mendel’s forgotten paper on trait inheritance, that German biologist Theodor Boveri recognized that the subcellular chromosomes he was studying in sea urchins were the units of heredity conceptualized by Mendel.
This is where our farm boy, Walter Sutton, came in and significantly extended the work of Boveri while still a graduate student. Sutton’s interest at the time was the process of meiosis – also a method of cell division like Flemming’s mitosis. But meiosis is a very special kind of cell division that yields the sex cells called gametes, either sperm or egg. The lubber grasshopper was an excellent model organism for Sutton since the gametes were large enough for him to observe and describe in detail, especially the intricate choreography of the chromosomes during mitosis and meiosis. Sutton was able to identify eleven pairs of chromosomes by their size, and to demonstrate that the gametes received one half of the pairs, so the number of chromosomes decreased during meiosis in a way that coincided with Mendel’s model for assortment and segregation. In the conclusion of his 1902 paper Sutton said: "I may finally call attention to the probability that the association of paternal and maternal chromosomes in pairs and their subsequent separation during the reducing division ... may constitute the physical basis of the Mendelian law of heredity". He was 24 years old.
The ecology of science in pre-WW1 America
Sutton’s Ph.D. advisor was the embryologist and America’s first cell biologist, Edmund Beecher Wilson, Professor of Zoology at Columbia University. E. B. Wilson got his Ph.D. at Johns Hopkins University, and went on to teach at Williams College, MIT, then Bryn Mawr before settling down at Columbia. Wilson was one of the editors of the journal in which both of Sutton’s papers were published, the Biological Bulletin of the Marine Biological Laboratory (MBL), Woods Holl, Mass. (That is not a typo. Apparently, Woods Hole went through numerous name changes with the original being Wood’s Holl, with an apostrophe.) Wilson was also a friend of Theodor Boveri.
Along with E. B. Wilson, the editorial staff for Volume IV of the Biological Bulletin included:
E. G. Conklin, a developmental biologist who was at the University of Pennsylvania at the time of Sutton’s publications. Conklin was educated at Ohio Wesleyan as well as Johns Hopkins Universities. One of his students was Aute Richards, husband of Mildred Hoge Richards, both of whom were mentioned in one of my earlier blog posts.
Jacques Loeb, a professor of physiology at the Universities of Chicago and California. He was Jewish, educated in Germany, and took up a position at Bryn Mawr College upon arriving in the US.
Thomas Hunt Morgan, of whom I’ve posted before and who we’ll discuss more later, received his Ph.D. from Johns Hopkins university and was at Bryn Mawr at the time of this publication, where he taught with Loeb before coming to Columbia University at Wilson’s request. Morgan was Mildred Hoge’s Ph.D. supervisor.
W. M. Wheeler, a professor of entomology at the University of Texas, Austin, who had spent time at Clark University (where he studied under Whitman, below) and University of Chicago, and would go on to be curator at the American Museum of Natural History in New York.
C. O. Whitman, a founding director of the MBL in Woods Hole, MA, and was at the time a professor and curator of the Zoological Museum at the University of Chicago. Before Chicago he was at Clark University in Worcester, MA, where his students included Wheeler and Lillie.
Frank R. Lillie, a zoologist and embryologist who was at the University of Chicago at the time. He was born in Canada, and moved to the US to study at the MBL in Woods Hole where he eventually became director. He was also a student of Whitman’s at Clark, after his initial summer at Woods Hole.
Looking at the backgrounds of these men, it becomes obvious that this was a pretty close-knit fraternity of scientists, and one can imagine that success in this field required entre to, or at least a good working relationship with this fraternity. Sutton’s fortuitous placement within this influential network was similar to Darwin’s social standing and close personal relationships with other high-ranking scientists in Victorian England, and contrasted with Mendel’s relative scientific isolation and the unfortunate fate of his paper.
We have followed the microscopy side of biology all the way into the first years of the 20th century and to Sutton's brilliant realization that chromosomes are the heritable factors Mendel predicted in the middle of the 19th century.
We can see these chromosomes under a microscope thanks to their affinity for anilene dyes, but what were they - and what were they made of?
The discovery of nucleic acids in chromosomes
In 1869, a Swiss physician Friedrich Miescher was studying proteins in cells when he stumbled on a substance within the nucleus that he called nuclein. Miescher worked in the laboratory of Felix Hoppe-Seyler who we discussed briefly in an earlier post here. We know Seyler today as the founder of modern biochemistry so Miescher could not have picked a better mentor to work with to understand proteins in a cell. But Miescher’s isolation of nuclear contents yielded a large quantity of phosphate-rich acidic materials in the nucleus, thus his name, nuclein. Miescher’s protocol for isolating nuclear contents was novel, and naturally aroused skepticism, and Seyler demanded independent verification by two other scientists working in his lab. Miescher was not able to publish his findings until 1871, and it immediately became controversial despite the independent replication of his results.
At the time that Miescher struggled to publish his findings on nuclein, the Franco-Prussian War had broken out between a confederation of German states and the French Empire, and would last into 1871. The American Civil War had finished a few years earlier in 1865, and the mass mobilization of an industrialized society, advancements in technology and the resulting scale of slaughter were aspects of warfare that were never seen before. Towards the end of the war, the sieges of Atlanta and Richmond presaged the even greater slaughter, the trenches, and mechanization of World War I. During the Franco-Prussian War, the belligerents fielded as many men for a 6-month conflict as the Americans deployed during the 4 years of their conflict. The French casualties were similar to the American losses, but the Prussians came through the war with significantly fewer casualties, and decisively crushed the Second French Empire under Napoleon III. Some of the key German personalities and leaders during the war would be immortalized and their names emblazoned on the hulls of massive steel cruisers and battleships for the next generation of wars in the new century: Otto von Bismark, Helmut von Moltke, Emperor Wilhelm the Great... The aftermath of the war included international mistrust and simmering resentments, a newly powerful and unified German Empire, and the end of French hegemony. Other after-effects included a widespread international adoption of the Prussian systems of military education, organization, technology, strategy and tactics – and thus the seeds were sown for the Great Wars of the early 20th century.
This widespread distrust resulting from the Franco-Prussian War also strained international science relations and may have influenced resistance to Miescher’s discovery of a novel chemistry within the nucleus of cells. Another cause may have been the involvement of Miescher’s mentor, Hoppe-Seyler, in a previous scandal about the discovery in brain tissue of another novel chemical compound, made and published by one of his students. So, for different reasons than Mendel, Miescher found himself unfortunately isolated from the scientific community.
Miescher struggled as a chemist to gain acceptance of his nuclein by both other chemists and biologists. Chemists questioned whether this new compound was just an artifact of Miescher’s isolation protocol, and quibbled over the methods of repeating the assays. Cell biologists just didn’t believe a chemist had useful insights about the contents of a nucleus. Meanwhile, others began to slowly piece things together. For example, a botanist Eduard Zacharias combined Miescher’s nuclear extraction protocol with Flemming’s staining methods to show that Miescher’s nuclein co-localized with Flemming’s chromatin. Flemming himself speculated that nuclein and chromatin may be the same thing, referencing Zacharias’s work in his 1882 book.
But before all that, Miescher was already speculating in an 1874 publication that nuclein may be the substance which caused fertilization, and perhaps was essential to heredity. The rationales supporting his ideas, unfortunately, were only communicated to his uncle in private letters, and so Miescher’s contributions to science have unfairly been minimized and forgotten since. In fact, at the time of Sutton’s papers, Miescher’s work was already forgotten like Mendel’s, and would not resurface much if at all in the 20th century. This was unfortunate because Miescher could have answered the appropriate questions to Sutton’s proposal that chromosomes were the physical basis of Mendel’s heritable factors: what are these chromosomes, and what are they made of, and how do they carry the information of heredity?
Lost at an early age
It is fun to speculate about a lucky convergence of Miescher and Sutton's knowledge which might have accelerated our understanding of the molecular mechanics of the laws of inheritance. But that was not to come about until the middle of the 20th century.
Instead we have a uniquely brilliant farm kid studying chromosomes in the grasshoppers native to his midwest farmland, publishing brilliant observations in 1902 and concluding correctly that he was witnessing the physical carriers of Mendel's heritable factors. But this brilliant bit of biology was to go nowhere for decades. Missed opportunities.
Sutton left biology and went to the oil fields so he could go to medical school. In 1905 Sutton went back to Columbia and earned his MD in 1907. He spent a couple years as an intern at Roosevelt Hospital in New York City. Finally in 1909 he became an assistant professor of surgery at a new medical school at his alma mater, the University of Kansas. He also served during World War I, was commissioned as a first lieutenant in the US Army Medical Reserve Corps, and was stationed only forty miles from the front lines in Paris. He became chief of the surgical unit by the end of his tour of duty. He returned from Paris to the US in 1915 after making numerous surgical innovations, and was dead by 1916 at the age of 39 from appendicitis.