#mass mice | Explore Tumblr posts and blogs

o-craven-canto · 20 days ago

Text

Rough timeline of the discovery of genes and DNA

(mostly condensed from the first half of S. Mukherjee, The Gene: An Intimate History, 2016, and this 1974 paper)

1857-1864: Gregor Mendel experiments with breeding peas at the monastery of Brno. The results show that information about flower color, pod shape etc. is transmitted in discrete blocks that do not mix, and can persist unexpressed in a generation to manifest again in the next.

1865-1866: Mendel's results are published in a minor journal and effectively forgotten for 35 years. He corresponds with physiologist Carl von Nägeli, who dismisses them as "only empirical" (???).

1868: Unaware of Mendel's work, Darwin proposes pangenesis as mechanism of heredity: every body part produces "gemmules" that carry hereditary information and merge to form gametes. This does not explain how new traits aren't immediately diluted out of existence, or why acquired changes aren't inheritable.

1869: Friedrich Miescher extracts a mysterious substance from pus on used bandages and salmon sperm. He calls it nuclein (later: chromatin), as it seems to be concentrated in cell nuclei.

1878: Albrecht Kossel separates nuclein into protein and a non-protein component, which he calls nucleic acid, and breaks it down in five nucleotides.

1882: Darwin dies, bothered -- among other things -- by the lack of a plausible mechanism to transmit new variation. Legend has it that Mendel's paper lay on a bookshelf of his study, unread.

1883: August Weissmann, noting that mice with cut tails always give birth to fully-tailed mice, theorizes that hereditary information is contained in a "germplasm" fully isolated from the rest of the body, contra pangenesis. At each generation, only germplasm is transmitted, and gives separate rise to a somatic line, i.e. the body, which isn't.

ca. 1890: Studying sea urchin embryos in Naples, Theodor Boveri and Wilhelm von Waldeyer-Hartz notice large coiled masses of nuclein inside cell nuclei which can be dyed blue with aniline. They call them chromosomes, literally "colorful bodies". Simultaneously, Walter Sutton discovers chromosomes in grasshopper sperm.

1897: Hugo de Vries, after collecting hundreds of "monstrous" plant varieties near Amsterdam, realizes (also unaware of Mendel's work) that each trait is due to a single discrete particle of information, never mixing with the others, which he calls pangene in homage to Darwin. He also notices the appearance of completely new variants, which he calls mutants. In the same year, Carl Correns -- a former student of Nägeli, who had completely neglected to mention Mendel's work -- reproduces it exactly in Tubingen with pea and maize plants.

1900: Having finally found out about Mendel's publication, De Vries rushes to publish his model before he can be accused of plagiarism, which happens anyway. Correns does the same. Erich von Tschermak-Seysenegg also independently recreates Mendel's results with pea plants in Vienna. Come on, guys, this is embarassing.

1902: Boveri and Sutton independently propose that hereditary information is carried by chromosomes. Supporters of this hypothesis generally hold that information is carried by proteins, with the simpler nucleic acids (only 5 nucleotides vs. 20 aminoacids) serving as scaffold.

1905: William Bateson coins the word genetics to describe the field growing mostly from De Vries' work. He realizes it should be possible to deliberately select organisms for specific individual genes. Meanwhile, Boveri's student Nettie Stevens discovers in mealworms a strangely small chromosome that is found only in males -- chromosome Y. This is the first direct evidence that chromosomes do, in fact, carry genetic information.

1905-1908: Thomas Hunt Morgan and his students breed and cross thousands of fruit flies in a lab in New York. Contra Mendel, they notice that traits are not passed down in a completely independent way: for example, male sex and white eyes usually manifest together. This suggests that their information particles are attached to each other, so that the physically-closest traits are more likely (but not guaranteed!) to be transmitted together.

1909: Phoebus Levene and his coworkers break down nucleic acids by hydrolysis into sugars, phosphate, and nucleobases. They assume that nucleobases must repeat along a chain in a repetitive sequence. In a treatise on heredity, Wilhelm Johannsen shortens "pangene" to gene. It's a purely theoretical construct, with no known material basis.

1911: Using Morgan's data on trait linkage, his student Alfred Sturtevant draws the first genetic map, locating several genes along a fruit fly chromosome. Genetic information now has a physical basis, although not yet a mechanism of transmission.

1918: Statistician Ronald Fisher proposes that traits appearing in continuous gradients, such as height, can still be explained by discrete genes if multiple genes contribute to a single trait, resolving an apparent contradiction. (Six genes for height, for example, are enough to produce the smooth bell curve noticed half a century earlier by Francis Galton.)

ca. 1920: Bacteriologist Frederick Griffith is studying two forms of pneumococcus, a "smooth" strain that produces deadly pneumonia in mice (and people) and a "rough" strain that is easily dispatched by immunity. He finds out that if live "rough" pneumococci are mixed with "smooth" ones killed by heat, the "rough" can somehow acquire the deadly "smooth" coating from the dead.

1926: Hermann Muller, another student of Morgan, finds out he can produce arbitrary amounts of new mutant flies by exposing their parents to X-rays.

1928: Griffith describes the acquired "transformation" of bacteria in an extremely obscure journal.

1929: Levene identifies the sugars in "yeast nucleic acid" and "thymus nucleic acid" as ribose and deoxyribose, respectively. The two will henceforth be known as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).

ca. 1930: Theodosius Dobzhansky, who also had worked with Morgan, discovers in wild-caught fruit flies variations of wing size, eye structure etc. that are produced by genes arranged in different orders on the chromosome. This rearrangement is the first physical mechanism for mutation discovered.

1940: Oswald Avery repeats Griffith's experiments with pneumococci, looking for the "transforming principle". Filtering away the remains of the cell wall, dissolving lipids in alcohol, destroying proteins with heat and chloroform does not stop the transformation. A DNA-degrading enzyme, however, does. Therefore, it is DNA that carries genetic information.

1943: By mixing flies with different gene orders and raising the mixed populations at different temperatures, Dobzhansky shows that a particular gene order can respond to natural selection, increasing or decresing in frequency.

1944: Avery publishes his results on transforming DNA. Physicist Erwin Schrödinger writes a treatise (What Is Life?) in which he states, on purely theoretical ground, that genetic information must be carried by an "aperiodic crystal", stable enough to be transmitted, but with a sequence of sub-parts that never repeat.

1950: In Cambridge, Maurice Wilkins starts using X-ray diffraction to try and make a picture of the atomic structure of dried DNA (as Linus Pauling and Robert Corey had done earlier with proteins). He is later joined by Rosalind Franklin, who finds a way to make higher-quality pictures by keeping DNA in its hydrated state. By hydrolyzing DNA, Erwin Chargaff notes that the nucleobases A and T are always present in exactly the same amount, as if they were paired, and so are C and G -- but A/T and C/G can be different amounts.

1951: Pauling publishes a paper on the alpha-helix structure of proteins. Having attended talks by Wilkins and Franklin, James Watson and Francis Crick attempt to build a physical model of DNA, a triple helix with internal phosphate, but Franklin notes it's too unstable to survive.

1952: Alfred Hershey and Martha Chase mark the protein envelope of phage viruses with radioactive sulfur, and their DNA with radioactive phosphorus. The phosphorus, but not the sulfur, is transmitted to host bacteria and to the new generation of phages. This indicates that DNA is not just exchanged as "transforming principle", but passed down through generations.

1953: Pauling and Corey also propose a structure of DNA, but they make the same mistake as Watson and Crick. These receive from Wilkins an especially high-quality photo (taken in 1952 by either Franklin or her student Ray Gosling). Combining this picture with Chargaff's measurements, they conclude that DNA must be a double helix, with a sugar-phosphate chain outside, and nucleobases meeting in pairs on the inside (A with T, C with G). The complementary sequences of bases give a clear mechanism for the storage and replication of genetic information.

1950s: Jacques Monod and François Jacob grow the bacterium Escherichia coli alternately on glucose and lactose. While its DNA never changes, the RNA produced changes in step with the production of glucose-digesting and lactose-digesting enzymes. So DNA is not directly affected, but different sequences are copied onto RNA depending on need.

1958: Arthur Kornberg isolates DNA polymerase, the enzyme that builds new DNA strands in the correct sequence. By inserting into DNA a heavier isotope of nitrogen, Matthew Meselson and Franklin Stahl show that each strand remains intact, separating during replication and then serving as template for a new one.

1960: Sydney Brenner and Jacob purify messenger RNA from bacterial cells. This seems to copy the sequence of a single gene and carry it to ribosomes, where proteins are built. RNA must encode the sequence of aminoacids of a protein, presumably in sets of 3 nucleotides (the smallest that can specify 20 aminoacids).

1961-1966: Multiple labs working in parallel (Marshall Nirenberg-Heinrich Matthaei-Philip Leder, Har Khorana, Severo Ochoa) map every possible triplet of nucleotides to a corresponding aminoacid. Synthetic RNA is inserted into isolated bacterial ribosomes, and aminoacids are marked one at a time with radioactive carbon to check the sequence of the resulting proteins.

1970: Paul Berg and David Jackson manage to fuse DNA from two viruses into a single sequence ("recombinant DNA") using DNA-cutting enzymes extracted from bacteria.

1972-1973: Janet Mertz joins Berg and Jackson, and proposes inserting the recombinant DNA into the genome of E. coli, exploiting the bacterium for mass production. Herb Boyer and Stanley Cohen perform a similar experiment merging bacterial DNA, and linking it to an antibiotic-resistance gene so that the recombinant bacteria can be easily isolated.

1975-1977: Frederick Sanger isolates template strands of DNA to build new ones with DNA polymerase, but uses altered and marked nucleobases that stop polymerization. By doing so, then segregating the shortened sequences by length and recognizing their final base with fluorescence, it's possible to read the exact sequence of bases on a DNA strand.

#biology #history of science #longpost

341 notes · View notes