Anyone who lives with more than one member of Felis catus knows that our beloved felines love to smell each other’s anal…
On April 25, 1953, “MOLECULAR STRUCTURE OF NUCLEIC ACIDS: A Structure for Deoxyribose Nucleic Acid” was published in Nature. J. D. Watson and F. H. C. Crick’s work was a brilliant deduction based on the experimental findings of many others.
DNA is a sleek double helix, with “rungs” consisting of a purine base paired with a smaller pyrimidine base: adenine (A) with thymine (T) and guanine (G) with cytosine (C). Hydrogen bonds link the pairs, individually weak but in large numbers powerfully strong, like a zipper.
“It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material,” Watson and Crick wrote near the end of the one-page article, planting the seeds for modern biotechnologies like recombinant DNA, transgenic organisms, gene silencing and therapy, and CRISPR gene editing.
The April 1953 paper was groundbreaking yet a bit of a tease, a “save-the-date” of sorts to announce the discovery and briefly describe the structure, for much confirming work needed to be done. Six months later, Francis Crick eloquently laid out the clues in “Structure of the Hereditary Material,” in a Scientific American volume, “Genetics”: “A genetic material must carry out two jobs: duplicate itself and control the development of the rest of the cell in a specific way.” DNA encodes amino acid sequences comprising proteins, which impart traits.
On this anniversary of the famous paper, DNA Science revisits the discoveries that catalyzed Watson and Crick’s deduction of how a molecule could carry and transmit genetic information.
Early Thoughts on Trait Transmission
People must have noted family resemblances since we were scattered bands of hunter-gatherers. Then, the beginnings of agriculture revealed trait transmission across generations. Consider the origin of corn.
About 9,000 years ago, people in Mexico began fashioning what would become corn from teosinte, a wild, branching plant with tiny, tough kernels. Herbivores ate and released them in their droppings, seeding new plants. The early farmers grated teosinte seeds into flour. Perhaps they saved and propagated unusual plants that had larger, softer kernels, like they domesticated other crops.
With continual selection over many years for the tastiest and easiest-to-digest kernels, corn arose. Only a few genes distinguish the two plants. A variant of a gene called tb1 confers the shrub-like shape of teosinte; the variant in corn suppresses an ancestral tendency for lateral growth, resulting in the cornstalk. Another gene controls the pattern of deposition of silica (sand) and lignin (a carbohydrate) in kernels, hardening teosinte while softening corn.
Disappearing Traits in Hybrids
Like other farmers and gardeners, Gregor Mendel (1822–1884) wondered why some traits disappear in one generation yet reappear in the next, like flower color. As a child, Mendel tended fruit trees. He became interested in statistics, and eventually taught natural science at a monastery in Brno in the Czech Republic.
Mendel experimented, kneeling before the chosen plants, cutting off the stalks that house the pollen, then collecting and painting the pollen onto female plants. He’d place a bag over the altered plant and scribble in a tattered notebook the trait variants he’d crossed. He followed 7 traits in 24,034 plants, from 1857 to 1863, noting the ratios of phenotypes (visible traits) in offspring.
A trait seemingly disappearing in one generation but returning in the next suggested to Mendel that a unit of information transmitted the trait. He envisioned factors, “elementen,” with two manifestations that were inherited: tall versus short plants, green versus yellow peas. Elementen combined at each generation, one from the male and one from the female.
Mendel published his findings in 1866, but few people read the paper. In 1901, when three botanists independently read Mendel’s paper, they credited him with deducing the two basic laws of inheritance. What works for peas also underlies the inheritance of single-gene conditions in people.
Soiled Bandages, Moldy Bread, Sick Mice, and Blenders
The experiments that revealed the structure and function of DNA toggle through time because they converged from different disciplines.
Five years after Mendel’s paper was published, Swiss physician and biochemist Friedrich Miescher isolated nuclei from white blood cells (pus) on soiled bandages. The nuclei harbored an unusual acidic substance containing nitrogen and phosphorus. Miescher found in all sorts of cells, and named it nuclein in an 1871 paper, later changed to nucleic acid. Miescher’s contribution to the story of DNA also went unnoticed for years, while people attributed inherited disease to abnormal proteins, not the mysterious acidic bandage goop.
In 1902, English physician Archibald Garrod linked inherited disease and protein. He noted that patients with certain inborn errors of metabolism didn’t have certain enzymes, which are proteins that speed the rates of specific chemical reactions.
As researchers linked heredity and enzymes in other species, from fruit flies with unusual eye colors to bread molds with nutritional deficiencies, attention refocused on the nucleic acids.
DNA entered the picture after World War I, when Frederick Griffith (1871–1941), a medical officer at the British Ministry of Health, was investigating people who’d died during the influenza pandemic of 1918, many from bacterial pneumonia. When he noticed that some patients had more than one strain of Streptococcus pneumonia in their sputum, he thought of a way to investigate the situation.
Griffith infected mice with two types of bacteria: one with smooth surfaces that killed the mice swiftly, and rough bacteria that the immune system recognized and removed, so the mice lived. Griffith showed that instructions for the trait of killing ability passed from smooth to rough bacteria. Something in the smooth bacteria turned the normally tame rough bacteria into killers, which he named the “transforming principle.” Griffith’s papers, published in 1928, were discovered and appreciated years after his death, like those of Mendel. A bomb killed Griffith during the London blitz, when he was working in his lab.
The next chapter in the story of DNA happened in 1944, when Rockefeller University physician/geneticists Oswald Avery (1877–1955), Colin MacLeod (1909–1972), and Maclyn McCarty (1911–2005), showed that DNA is the transforming principle. They repeated Griffith’s experiments, with a twist. They added either an enzyme that destroys protein or an enzyme that destroys DNA. Smooth bacteria could transform rough bacteria into killers when their protein was destroyed, but not when their DNA was destroyed.
Alfred Hershey (1908–1997) and Martha Chase (1927–2003), at the Cold Spring Harbor Laboratory on Long Island, finally ruled out protein as the genetic material. They infected bacteria with viruses grown on medium containing either radioactive phosphorus (found in nucleic acids but not the amino acids of proteins) or sulfur, found in amino acids but not in nucleic acids. Whichever marked molecule prevailed from bacterial generation to generation would indicate the nature of the genetic material.
The protocol became known as “blender experiments” because Hershey and Chase infected bacteria with the viruses, then poured the preparations into small tubes that were spun in a centrifuge, which is actually more like a clothing dryer than a blender. The oscillation shook off the viral protein coats clinging to the infected bacteria, which rose to the surface. Meanwhile viral DNA entered the cells, which sunk to the bottom of the tubes.
When the radioactive sulfur ended up in the floating protein coats while the radioactive phosphorus in bacteria settled down, Hershey and Chase had their answer. The genetic material is DNA, and not protein.
From Chemistry to Crystallography to Cardboard Cutouts
Chemical studies paralleled those probing white blood cells, bacteria, and their viruses.
In 1909, Russian-American biochemist Phoebus Levene identified the 5-carbon sugar ribose in RNA, and then deoxyribose in DNA. He discovered that the four main parts of a nucleic acid building block (a nucleotide), a 5-carbon sugar, a nitrogen-containing base (A, T, C, or G), a phosphorus-containing phosphate, and a hydroxyl (OH) group, are present in about equal proportions. He further deduced that a nucleotide had one of each part, how nucleotides pair, and that the sugar-phosphate “backbone” was always the same, but the nitrogen-containing bases were of four types, like a language.
Although the four DNA base types had to be present in different amounts to encode information, Austrian-American biochemist Erwin Chargaff showed in the early 1950s that DNA in several species contains equal amounts of A and T and of G and C. That’s consistent with pairs of bases imparting information.
Next, English physicist Maurice Wilkins, English chemist Rosalind Franklin, and student Raymond Gosling bombarded DNA with X-rays, generating a diffraction pattern that revealed a helix. Accounts differ on who discovered what, but somehow when Gosling showed Franklin’s elegant “photo 51” to Wilkins, who showed it to Watson at the end of January in 1953, the men realized that the remarkable symmetry of the molecule best fit the shape of a highly regular helix. Franklin’s role has been downplayed, as if she discovered the helix but didn’t realize what she’d found, for misogyny at the time was a backdrop to the fondness of some of the male researchers for glory. A report illuminating Franklin’s contribution will be published next week.
With the helix reveal, the race to fill-in-the-blanks intensified. In February, famed biochemist Linus Pauling suggested a triple helix structure for DNA. That was incorrect.
Watson and Crick, certain of the sugar-phosphate backbone from photo 51, turned their attention to the bases, the source of the information, using cardboard cutouts.
On Saturday morning, February 28, while waiting for Crick to show up for a meeting, Watson moved the cutouts around, pairing A with A, then A with G. Only A next to T, and G next to C, led to a sleek helix. When Crick arrived 40 minutes later, the two quickly realized that all the pieces fit. The famed cheesy portrait of Watson and Crick with the “ball-and-stick” metal model, with Crick pointing a slide rule, was staged.
In “Structure of the Hereditary Material” penned 6 months later, Crick’s thinking unfurled:
• Proteins and DNA are huge, but have only a few types of building blocks.
• The molecules have a handedness – that is, mirror images of their three-dimensional forms do not exist. So shape is important.
• All organisms have DNA, the amount consistent in a species.
Crick explained, somewhat redundantly, “The problem is rather like a 3D jigsaw puzzle with curious pieces joined together by rotatable joints.” Then he considered the mounting physical evidence.
• X-ray diffraction reveals a helix.
• The bases are on the inside.
• The chains run in opposite directions.
• The base pairs have a consistent width, A with T and G with C.
The “model … immediately suggests how the DNA might produce an exact copy of itself.” The halves separate, part, and bring in new bases, like a line of dancing couples parting and choosing new partners. Five years later, experiments by Matthew Meselson and Franklin Stahl would visualize replicating DNA.
Crick was quite prescient. He predicted unwinding proteins to untwist the millions of turns of a chromosome’s DNA; a mechanism to repair breaks; and perhaps most importantly, how a DNA sequence encodes information:
“We suspect that the sequence of bases acts as a kind of genetic code. Such an arrangement can carry an enormous amount of information. If we imagine that the pairs of bases correspond to the dots and dashes of the Morse code, there is enough DNA in a single cell of the human body to encode about 1,000 large textbooks.”
That really hits home for me, the author of many textbooks. Rarely is science so elegant. On this anniversary, I’m awed anew.