4406 entries. 94 themes. Last updated December 26, 2016.

Heredity / Molecular Biology / Genomics Timeline

Theme

2,800,000 BCE – 8,000 BCE

The Oldest Almost Complete Mitochondrial Genome Sequence of a Hominin Circa 400,000 BCE

The "Homo Heidelbergensis Cranium 5" from Sima de los Huesos in Spain.

The exterior of the Denivosa Cave

Molar found in Denisova Cave of the Altay Mountains in Southern Siberia.

On December 4, 2013 Matthias Meyer, Eduald Carbonell and Svante Pääbo and colleagues reported that the almost complete mitochondrial genome sequence of a hominin from Sima de los Huesos in Spain, dating back roughly 400,000 years, shows that it is closely related to the lineage leading to mitochonrial genomes of Denisovans, an eastern Eurasian sister group to Neanderthals.

"The fossil, a thigh bone found in Spain, had previously seemed to many experts to belong to a forerunner of Neanderthals. But its DNA tells a very different story. It most closely resembles DNA from an enigmatic lineage of humans known as Denisovans. Until now, Denisovans were known only from DNA retrieved from 80,000-year-old remains in Siberia, 4,000 miles east of where the new DNA was found.

"The mismatch between the anatomical and genetic evidence surprised the scientists, who are now rethinking human evolution over the past few hundred thousand years. It is possible, for example, that there are many extinct human populations that scientists have yet to discover. They might have interbred, swapping DNA. Scientists hope that further studies of extremely ancient human DNA will clarify the mystery" (http://www.nytimes.com/2013/12/05/science/at-400000-years-oldest-human-dna-yet-found-raises-new-mysteries.html?hp&_r=0, accessed 12-04-2013).

Meyer et al, "A mitochondrial genome sequence of a hominin from Sima de ls Huesos", Nature (2013) doi:10.1038/nature12788.

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The First Complete Neanderthal Genome Sequence Circa 128,000 BCE

Svante Pääbo.

A map of the Altai Mountain range.

On December 18, 2013 Svante Pääbo and colleagues from the Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology in Leipzig, together with scientists from research centers in America, China, Russia and other countries, announced that they sequenced the complete genome of a 130,000 year old Neanderthal woman from a single toe found in a Siberian cave in the Altai Mountains. There DNA evidence has been unusually well preserved because of very low average temperature. Comparison of this complete Neanderthal genome with those of 25 modern humans enabled the authors to compile a list of mutations that evolved in modern humans after their ancestors branched off from Neanderthals some 600,000 years ago. "The list of modern human things is quite short," said John Hawks, a paleoanthropologist at the University of Wisconsin who was not involved in the study. The paper, published in the journal Nature, was entitled "The complete genome sequence of a Neanderthal from the Altai Mountains"  doi:10.1038/nature12886.

The abstract read as follows:

"We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans."

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Scientists Sequence Woolly Mammoth Genome--the First of an Extinct Animal Circa 100,000 BCE

The largest European specimen of a Wooly Mammoth.

A Steppe Mammoth skull in Sibera.

A male Asian Elephant in India.

A chart from the Mammoth Genome Project depicting gene-encoding bases on chromosomes of both a human and a mammoth. 

On November 19, 2008 scientists from the Mammoth Genome Project at Pennsylvania State University, University Park, reported the genome-wide sequence of the woolly mammoth, an extinct species of elephant that was adapted to living in the cold environment of the northern hemisphere.  The woolly mammoth, Mammuthus primigenius, was a species of mammoth, the common name for the extinct elephant genus Mammuthus. One of the last in a line of mammoth species, it diverged from the steppe mammothM. trogontherii, about 200,000 years ago in eastern Asia. Its closest extant relative is the Asian elephant.

The genome sequence of the woolly mammoth was the first sequence of the genome of an extinct animal, and it opened up the possibility of reconstructing species from the last Ice Age.

"They sequenced four billion DNA bases using next-generation DNA-sequencing instruments and a novel approach that reads ancient DNA highly efficiently."

'Previous studies on extinct organisms have generated only small amounts of data," said Stephan C. Schuster, Penn State professor of biochemistry and molecular biology and the project's other leader. "Our dataset is 100 times more extensive than any other published dataset for an extinct species, demonstrating that ancient DNA studies can be brought up to the same level as modern genome projects' (quoted from Genetic Engineering and Biotechnology News accessed 11-21-2008).

" 'By deciphering this genome we could, in theory, generate data that one day may help other researchers to bring the woolly mammoth back to life by inserting the uniquely mammoth DNA sequences into the genome of the modern-day elephant,' Stephan Schuster of Pennsylvania State University, who helped lead the research, said in a statement." (quoted from Reuters 11-19-2008, accessed 11-21-2008).

"The appearance and behaviour of this species are among the best studied of any prehistoric animal due to the discovery of frozen carcasses in Siberia and Alaska, as well as skeletons, teeth, stomach contents, dung, and depiction from life in prehistoric cave paintings. Mammoth remains had long been known in Asia before they became known to Europeans in the 17th century. The origin of these remains was long a matter of debate, and often explained as being remains oflegendary creatures. The animal was only identified as an extinct species of elephant by Georges Cuvier in 1796." (Wikipedia article on Woolly Mammoth, accessed 10-31-2013).

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The Denisova Hominin, a Third Kind of Human Circa 39,000 BCE

Molar found in Denisova Cave of the Altay Mountains in Southern Siberia. (Click on image to view larger.)

The Family Tree - Neanderthals and Denisovans were closely related. DNA comparisons suggest that our ancestors diverged from theirs some 500,000 years ago. (Click on image to view larger.)

 

 A Tale of Three Humans

A third kind of human, called Denisovans, seems to have coexisted in Asia with Neanderthals and early modern humans. The latter two are known from abundant fossils and artifacts. Denisovans are defined so far only by the DNA from one bone chip and two teeth—but it reveals a new twist to the human story.

Chip Clark, Smithsonian Institution.

On March 24, 2010 scientists announced the discovery of a finger bone fragment of an eight year old girl who lived about 41,000 years ago, found in the remote Denisova Cave in the Altai Mountains in Siberia, a cave which was also inhabited by Neanderthals and modern humans. Discovery of two teeth and a toe bone belonging to different members of the same population were later reported.These three objects are the only specimens from which the Denisova hominins are known. The average annual temperature of Denisova Cave remains at 0°C (32°F), a factor which contributed to the preservation of archaic DNA among the diverse prehistoric remains discovered, in addition to the Denisova hominin remains. 

Using a new technique for sequencing ancient DNA from bone, in August 2012 scientists from the Max Planck Institute reconstructed the genome of the Denisova hominins and announced that they were a new species, that they interbred with our species, and that the DNA results suggest that they had dark hari, eyes, and skin.  

"Analysis of the mtDNA of the finger bone showed it to be genetically distinct from the mtDNAs of Neanderthals and modern humans [Katsnelson 2010]. However, subsequent study of the genome from this specimen suggests this group shares a common origin with Neanderthals. They ranged from Siberia to Southeast Asia, and they lived among and interbred with the ancestors of some present-day modern humans, with up to 6% of the DNA of Melanesians and Australian Aboriginies deriving from Denisovans.

"It was in 2008 when Russian archaeologists discovered the finger bone fragment, and nick-named it 'X Woman'. Artifacts, including a bracelet, excavated in the cave at the same level were carbon dated to approximately 40,000 BP.

"A team of scientists led by Johannes Krause and Svante Paabo from the Max Planck Institute in Germany sequenced mtDNA from the fragment. The analysis indicated that modern humans, Neanderthals and the Denisova hominin last shared a common ancestor around 1 million years ago [Katsnelson 2004].

"The mtDNA analysis further suggested this new hominin species was the result of an early migration out of Africa, distinct from the later out-of-Africa migrations associated with Neanderthals and modern humans. Some argue it may be a relic of the earlier African exodus of Homo erectus, because of the tooth size, although this has not been proved. The conclusions of both the excavations and the sequencing are still debatable because the evidence shows that the Denisova Cave has been occupied by all three human forms" (http://www.bradshawfoundation.com/origins/denisova_hominin.php, accessed 07-07-2013).

For images and a very readable account of these discoveries see "The Case of the Missing Ancestor," nationalgeographic.com, July, 2013.

 

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Neanderthal Genome Reveals Interbreeding with Humans Circa 36,000 BCE

Svante Pääbo

In May 2010 paleogeneticist Svante Pääbo and colleagues at the Max Planck Institute for Evolutionary Anthropology in Leipzig published a draft genome sequence of DNA obtained from Neanderthal bones recovered from Vindija Cave that were around 38,000 years old. Neanderthal fossils found in this cave near the city of VaraždinCroatia, are among the best preserved in the world.

In their preliminary draft of the Neanderthal genome announced in February 2009 the scientists indicated that

"Previous mitochondrial analysis of Neanderthal DNA has uncovered no sign that Neanderthals and humans interbred sufficiently to leave a trace. A preliminary analysis across the new genome seems to confirm this conclusion, but more sequence data could overturn this conclusion" (http://www.newscientist.com/article/dn16587-first-draft-of-neanderthal-genome-is-unveiled.html#.UnKcfFCsim4. accessed 10-31-2013). 

However, comparison in 2010 of the full Neanderthal sequence with that of modern humans suggested that there was some interbreeding between Homo neanderthalensis and Homo sapiens.

"Bone contains DNA that survives long after an animal dies. Over time, though, strands of DNA break up, and microbes with their own DNA invade the bone. Pääbo's team found ways around both problems with 38,000 and 44,000-year-old bones recovered in Croatia: they used a DNA sequencing machine that rapidly decodes short strands and came up with ways to get rid of the microbial contamination.

"They ended up with short stretches of DNA code that computers stitched into a more complete sequence. This process isn't perfect: Pääbo's team decoded about 5.3 billion letters of Neanderthal DNA, but much of this is duplicates, because – assuming it's the same size as the human genome – the actual Neanderthal genome is only about 3 billion letters long. More than a third of the genome remains unsequenced. . . .

"Any human whose ancestral group developed outside Africa has a little Neanderthal in them – between 1 and 4 per cent of their genome, Pääbo's team estimates. In other words, humans and Neanderthals had sex and had hybrid offspring. A small amount of that genetic mingling survives in "non-Africans" today: Neanderthals didn't live in Africa, which is why sub-Saharan African populations have no trace of Neanderthal DNA" (http://www.newscientist.com/article/dn18869-neanderthal-genome-reveals-interbreeding-with-humans.html#.UnKfSFCsim4, accessed 10-31-2013).

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1100 – 1200

Jewish Bodies Found in Medieval Well in Norwich, England Circa 1150 – 1250

In 2004 the skeletons of 17 bodies were found at the bottom of a medieval well during the excavation of a site in the center of Norwich, England ahead of the construction of a shopping center. The remains were put into storage and investigated in 2011 by a team led by Scottish forensic anthropologist Sue Black.

Using DNA sequencing, molecular palaeobiologist Ian Barnes determined that the skeletons, which date to the 12th or 13th century, were probably remains of Jews. Eleven of the 17 skeletons were those of children aged between two and 15. The remaining six were adult men and women. It is likely that they were murdered or forced to commit suicide.

"Pictures taken at the time of excavation suggested the bodies were thrown down the well together, head first.

"A close examination of the adult bones showed fractures caused by the impact of hitting the bottom of the well. But the same damage was not seen on the children's bones, suggesting they were thrown in after the adults who cushioned the fall of their bodies.

"The team had earlier considered the possibility of death by disease but the bone examination also showed no evidence of diseases such as leprosy or tuberculosis.

"Giles Emery, the archaeologist who led the original excavation, said at first he thought it might have been a plague burial, but carbon dating had shown that to be impossible as the plague came much later.

"And historians pointed out that even during times of plague when mass graves were used, bodies were buried in an ordered way with respect and religious rites.

"Norwich had been home to a thriving Jewish community since 1135 and many lived near the well site. But there are records of persecution of Jews in medieval England including in Norwich.

"Sophie Cabot, an archaeologist and expert on Norwich's Jewish history, said the Jewish people had been invited to England by the King to lend money because at the time, the Christian interpretation of the bible did not allow Christians to lend money and charge interest. It was regarded as a sin.

"So cash finance for big projects came from the Jewish community and some became very wealthy - which in turn, caused friction" (http://www.bbc.co.uk/news/uk-13855238, accessed 01-07-2014). This article contains a dramatic image of the way the skeletons were found in the well.

In June and July 2011 the BBC televised a one hour episode of the series History Cold Case, Series 2, entitled The Bodies in the Well. In January 2014 this show was downloadable from iTunes for a fee. 

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1700 – 1750

Pierre-Louis Moreau de Maupertuis' Pioneer Theory of Epigenesis and Biparental Heredity 1744 – 1745

Pierre Louis Maupertuis

Venus Physique by Maupertuis

Dissertation physique a l'occasion du negre blanc by Maupertuis

In 1744 French mathematician, philosopher and man of letters Pierre-Louis Moreau de Maupertuis issued anonymously Dissertation physique a l'occasion du negre blanc in Leiden through an unidentified publisher. This small book on human heredity was inspired by the appearance in Paris of a young albino negro. The case prompted Maupertuis to search for other cases of abnormal traits being passed down in a family from one generation to the next.  The following year he explored the issue of human heredity more fully in his Venus physique which incorporated a reprint of the 1744 Dissertation.

Issued anonymously in 1745, and without publishing location or the name of its printer, Venus physique refuted the preformationist theories of embryonic development held by most of his contemporaries in favor of the then-discredited epigenetic hypothesis, which Maupertuis had adopted after considering the obvious facts of biparental heredity.  Maupertuis rejected all vitalist or spiritual interpretations of the hereditary mechanism, arguing that biparental heredity required corporeal contributions from each parent. This argument was based on research that Maupertuis performed shortly after his arrival in Berlin in 1740, when he began collecting the pedigrees of the polydactylous Ruhe family. These pedigrees showed that the abnormal trait could be passed either by the male or female parent and that the trait tended to weaken and disappear over time as polydactylous individuals continued to marry normal spouses.  According to Glass, Maupertuis's theories of biparental heredity and epigenesis substantially anticipated those of Darwin, Mendel and de Vries nearly a century and a half later.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 215.1.

Glass, "Maupertuis, pioneer of genetics and evolution," Forerunners of Darwin 1745-1859, ed. Glass, Temkin & Straus (1968) 51-83.

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1800 – 1850

Lamarck Issues the First Published Statement of Lamarckism 1801

A portrait of Jean Baptiste Pierre Antoine de Monet, Chevalier de Lamarck

Systême des animaux sans vertèbres

In 1801 French soldier, biologist, and naturalist Jean Baptiste Pierre Antoine de Monet, Chevalier de Lamarck published Systême des animaux sans vertèbres. The "Discours d'overture" occupying the first forty-eight pages of this work contained Lamarck's first published statement of his evolutionary theory of species development, including his idea of the continuous progressive perfection of species from the simplest to the most complex, and his famous theory of the inheritance of acquired characteristics, generally called "Lamarckism."  The Systême was also the first zoological work to employ the term "invertebrates" to describe what had previously been lumped under the imprecise category of "insects and worms."

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) No. 215.5.

Hook & Norman, The Haskell F. Norman Library of Science & Medicine (1991) no. 1261.

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Lamarck's Most Extensive Exposition of his Theory of the Inheritance of Acquired Characteristics 1809

A portrait of Jean-Baptiste Lamarck by Charles Thévenin

Philosophie Zoologique by Lamarck

In 1809 French naturalist and biologist Jean-Baptiste Pierre Antoine de Monet, Chevalier de Lamarck published Philosophie zoologique. This 2-volume work was Lamarck's most extensive presentation of his evolutionary theory of species development. The work was divided into three parts, the first two of which contained a more elaborate analysis of the evidence for increasing levels of complexity, and a more detailed discussion of Lamarck's two-factor theory than his original brief exposition of 1801. The third part provided a very detailed extension of these earlier theories: the problem of a physical explanation (as opposed to a philosophical or religious one) for the emergence of the higher mental faculties. Lamarck's explanation linked mind's progressive development to an increasing structural complexity of the nervous system— a necessary and crucial argument for including man among the products of evolutionary processes.  For Lamarck, the development of the nervous system was one of the most important events in the evolutionary process, as it was at that point, according to his theory, that animals began to conceive ideas and control their movements, thus enabling them voluntarily to form the habits (such as stretching the neck up to feed on high branches) that would eventually result in the development of new organs.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) No. 216. 

Hook & Norman, The Haskell F. Norman Library of Science & Medicine (1991) No. 1267.

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Joseph Adams Issues a Pioneering Work on Medical Genetics 1814

In 1814 English physician and surgeon and medical writer Joseph Adams of London published A Treatise on the Supposed Hereditary Properties of Diseases, Containing Remarks on the Unfounded Terros and Ill-Judged Cautions Consequent on such Erroneous Opinion; with notes, illustrative of the Subject, Particularly in Madness and Scrofula.  A pioneer in medical genetics, Adams distinguished between familial and hereditary diseases, saw that an increase in hereditary disease frequency in isolated areas could be caused by inbreeding, and suggested the establishment of hereditary disease registers.

J. Norman (ed), Morton's Medical Bibliography 5th ed (1991) no. 216.1.

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William Charles Wells Publishes the First Recognizable Statement of the Theory of Natural Selection 1818

In 1818, a year after the death of Scottish American physician and scientist, William Charles Wells, his Two Essays: One upon Single Vision with Two Eyes; the Other on Dew. A Letter to the Right Hon. Lloyd, Lord Kenyon and an Account of a Female of the White Race of Mankind, Part of whose Skin Resembles that of a Negro was published in London. Wells’s “Account of a female of the white race. . . ." was read before the Royal Society in 1813, but first appeared in print posthumously. It contained the first recognizable statement of the principle of natural selection. In his study of an albino negro woman, Wells assumed a biological evolution of the human species, drawing an analogy between man’s selective breeding of domestic animal varieties and nature’s selection of varieties of men best suited to various climates.  He wrote,

"[What was done for animals artificially] seems to be done with equal efficiency, though more slowly, by nature, in the formation of varieties of mankind, fitted for the country which they inhabit. Of the accidental varieties of man, which would occur among the first scattered inhabitants, some one would be better fitted than the others to bear the diseases of the country. This race would multiply while the others would decrease, and as the darkest would be the best fitted for the [African] climate, at length [they would] become the most prevalent, if not the only race."

Neither Charles Darwin nor Alfred Russel Wallace was familiar with Wells’s paper when they formulated the theory of natural selection, but after Darwin published the Origin in 1859 Wells' paper was called to his attention, and Darwin paid tribute to Wells’s pioneering statement in the historical introduction to the third edition of the Origin. Wells’s paper was contained in the first collected edition of his essays on binocular vision and on dew formation, both of which represented advances in the knowledge of these subjects.

Hook & Norman, The Haskell F. Norman Library of Science and Medicine (1991) no. 2200.

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William Lawrence Describes the Natural History of Man 1819

William Lawrence

The Court of Chancery during the reign of George I by Benjamin Ferrers

Surgeon and scientist William Lawrence published Lectures on Physiology, Zoology and the Natural History of Man in 1819. This work set out Lawrence’s radical—and to our eyes, remarkably advanced—ideas concerning evolution and heredity. Arguing that theology and metaphysics had no place in science, Lawrence relied instead on empirical evidence in his examination of variation in animals and man, and the dissemination of variation through inheritance. On the question of cause, Lawrence disagreed with those who ascribed variation to external factors such as climate, and rejected the Lamarckian notion of the inheritance of acquired characteristics. His understanding of the mechanics of heredity was well ahead of his time: he stated that “offspring inherit only [their parents’] connate qualities and not any of the acquired qualities,” and that the “signal diversities which constitute differences of race in animals . . . can only be explained by two principles . . . namely, the occasional production of an offspring with different characters from those of the parents, as a native or congenital variety; and the propagation of such varieties by generation” (p. 510).

While Lawrence did not grasp the role that natural selection plays in the origination of new species, he recognized that “selections and exclusions,” including geographical separation, were the means of change and adaptation in all animals, including humans. He noted that men as well as animals can be improved by selective breeding, and pointed out that sexual selection was responsible for enhancing the beauty of the aristocracy: “The great and noble have generally had it more in their power than others to select the beauty of nations in marriage; and thus . . . they have distinguished their order, as much by elegant proportions of person, as by its prerogatives in society” (p. 454). He investigated the human races in detail, and insisted that the proper approach to this study was a zoological one, since the question of variation in mankind “cannot be settled from the Jewish Scriptures; nor from other historical records” (p. 243).

The Natural History of Man came under fire from conservatives and clergy for its materialist approach to human life, and Lawrence was accused of atheism for having dared to challenge the relevance of Scripture to science. In 1822 the Court of Chancery ruled the Natural History blasphemous, thus revoking the work’s copyright. Lawrence was forced to withdraw the book, a fact reflected in the comparative rarity of the first edition. However, the book’s notoriety was such that several publishers issued their own pirated editions, keeping the work in print for several decades. A list of the London editions of Lawrence’s work, taken from OCLC, follows:

1819 J. Callow (authorized)

1819 s.n. (?)

1822 W. Benbow

1822 J. Smith

1822 Kaygill & Price (unillustrated)

1823 R. Carlile

1823 J. Smith

1834 J. T. Cox

1838 J. Taylor

1840 J. Taylor

1844 J. Taylor

1848 H. G. Bohn

1866 Bell & Daldy

Editions were also published in Edinburgh and America. Darwin owned one of the unauthorized editions listed above, the one issued by “the notorious shoemaker-turned-publisher William Benbow, who financed his flaming politics by selling pornographic prints” (Desmond & Moore, Darwin, p. 253). Darwin was obviously impressed with Lawrence’s work, citing it five times in The Descent of Man (1871). 

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Production of the First Protein Crystals 1840

Crystals of plant and animal products do not typically occur naturally. In 1840 F. L. Hünefeld published his accidental observation of the first protein crystals— those of hemoglobin—in a sample of dried menstrual blood pressed between glass plates.

Hünefeld, Der Chemismus in der thierischen Organisation, Leipzig: Brockhaus, 1840, 158-63.

Lesk, Protein Structure, 36. Tanford & Reynolds, Nature’s Robots, 22. Judson, Eighth Day of Creation, 489.

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Steenstrup's Theory of Alternation of Generations or Metagenesis 1842

A portrait of Japetus Steenstrup 

In 1842 Danish zoologist and biologist in København Johannes Japetus Smith Steenstrup published Om Fortplantning og Udvikling gjennem vexlende Generations-raekker. In this work Steenstrup expounded the the theory of the alternation of generations, or alternation of phases or metagenesis. He showed that certain animals produce offspring which never resemble them but which, on the other hand, bring forth progeny which return in form and nature to their grandparents or more distant ancestors. 

J. Norman (ed) Morton's Medical Bibliography (1991) no. 217.

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The Relationship Between Optical Activity, Crystalline Structure and Chemical Composition 1847

In his dissertation published in 1847 French chemist and microbiologist Louis Pasteur reported a series of “investigations into the relation between optical activity, crystalline structure, and chemical composition in organic compounds, particularly tartaric and paratartaric acids. This work focused attention on the relationship between optical activity and life, and provided much inspiration and several of the most important techniques for an entirely new approach to the study of chemical structure and composition. In essence, Pasteur opened the way to a consideration of the disposition of atoms in space.” (DSB)

Pasteur, Thèses de physique et de chimie, Presentées à la Faculté des Sciences de Paris. Paris: Bachelier, 1847.

Lesk, Protein Structure, 36.

Hook & Norman, The Haskell F. Norman Library of Science & Medicine (1991) no. 1652.

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1850 – 1875

Darwin & Wallace Issue the First Printed Exposition of the Theory of Evolution by Natural Selection August 20, 1858

Charles Darwin

Alfred Russel Wallace

A diagram of natural selection

Living barnacles

On August 20, 1858 Charles Darwin and Alfred Russel Wallace published "On the tendency of species to form varieties; and on the perpetuation of varieties and species by natural selection" in the Journal of the Proceedings of the Linnean Society. This was the first printed formal exposition of the theory of evolution by natural selection. Darwin had developed the essential elements of his theory by 1838 and set them on paper in 1844; however, he chose to keep his work on evolution unpublished for the time, instead concentrating his energies first on the preparation for publication of his geological work on the Beagle voyage , and then on an exhaustive eight-year study of the barnacle genus Cirripedia.

In 1856, at the urging of Charles Lyell, Darwin began writing a vast encyclopedic work on natural selection; however, it is possible that the extremely cautious Darwin might never have published his evolutionary theories during his lifetime had not Alfred Russel Wallace, a naturalist born in New Zealand, independently discovered the theory of natural selection. Wallace conceived the theory of natural selection during an attack of malarial fever in Ternate in the Mollucas, Indonesia (Febuary, 1858) and sent a manuscript summary to Darwin, who feared that his discovery would be pre-empted.

In the interest of justice Joseph Dalton Hooker and Charles Lyell suggested joint publication of Wallace's paper prefaced by a section of a manuscript of a work on species written by Darwin in 1844, when it was read by Hooker, plus an abstract of a letter by Darwin to Asa Gray, dated 1857, to show that Darwin's views on the subject had not changed between 1844 and 1857. The papers by Darwin and Wallace were read by Lyell before the Linnean Society on July 1, 1858 and published on August 20.

"There are five different forms in which the original edition can be found, but they are all from the same setting of type. Four of these are the results of the publishing customs of the Linnean Society of London and the fifth is the authors' offprints. The Journal came out in parts and was available to Fellows of the Society with Zoology and Botany together in each part, Zoology alone, or Botany alone. Later it appeared in volume form made up from reserved stock of the parts with new title pages, dated in the year of completion of the volume, and indexes. This again was available complete or as Zoology or Botany alone. The Zoology was signed with numbers and the Botany with letters. The Darwin-Wallace paper occurs in the complete part in blue wrappers, or in the Zoology part in pink wrappers; the Botany parts were in green. The Linnean Society has all the forms in its reference files, although it does not hold the offprint.

"The authors' offprints were issued in buff printed wrappers with the original pagination retained. They have 'From the Journal of the Proceedings of the Linnean Society for August 1858.' on page [45]. They were printed from the standing type but, presumably, after the copies of the number had been run off. The only copies which I have seen have been inscribed personally by Darwin, but Life and letters, Vol. II, p. 138, notes that Darwin had sent eight copies to Wallace, still in the far-east, and had kept others for him" (http://darwin-online.org.uk/EditorialIntroductions/Freeman_TendencyofVarieties.html, accessed 11-25-2014).

On November 24, 2014, as a result of an international collaboration with the Darwin Manuscript Project based at the American Museum of Natural History, New York, Cambridge University's Cambridge Digital Library published online more than 12,000 hi-resolution images of manuscripts by Darwin, with transcriptions and detailed notes. These papers chart the evolution of Darwin’s intellectual journey, from early theoretical reflections while on board HMS Beagle, to the publication of On the Origin of Species 155 years earlier, on November 24, 1859. The papers document the origins of Darwin’s theory of evolution – including the pages where he first coined and committed to paper the term "natural selection." 

J. Norman (ed.), Morton's Medical Bibliography[1991] no. 119.  Hook & Norman, The Haskell F. Norman Library of Science and Medicine (1991) no. 591.

(This entry was last updated on 11-25-2014)

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Charles Darwin's "On the Origin of Species by Means of Natural Selection" November 24, 1859

The title page of On the Origin of Species by Charles Darwin

Charles Darwin

On November 24, 1859 Charles Darwin issued through the London publisher, John Murray, his book entitled On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. From its original publication, through the early years of the twenty-first century, this work remained one of the most widely appreciated, or disputed, classics in the history of science.

The idea of species evolution can be traced as far back as the ancient Greek belief in the "great chain of being". Darwin's great achievement was to make this centuries-old "underground" concept acceptable to the scientific community and educated readers by cogently arguing for the existence of a viable mechanism— natural selection— by which new species evolve over vast periods of time.  Darwin's work contained only a single illustration- a branching evolutionary tree, the first known presketch of which appears in Darwin's notebooks in 1839.

Though Darwin stated his case for evolution by natural selection persuasively and in the most diplomatic of tones, the work evoked a storm of controversy, causing Darwin to revise it through six editions during his lifetime. Since its publication the scientific evidence supporting evolution by natural selection has reached a massive—even overwhelming— preponderance, yet the controversy over evolution has never abated.

There is only one issue of the first edition of On the Origin of Species, and although three cloth binding and advertisement variants have been identified, no priority has been established. 1250 copies were printed, of which about 1,170 were available for sale; the remainder consisted of 12 author's copies, 41 review copies, 5 copyright copies, and "Darwin required ninety copies to be sent as presentations to friends, family, and scientists [Correspondence, 8: 554-6]" (Kohler & Kohler, see below, 333). Following Darwin's instructions, these presentation copies were sent out by the publisher, usually inscribed "From the Author" by the publisher's clerk.  The book was offered to booksellers two days earlier on November 22, and oversubscribed by 250 copies causing John Murray to propose a new edition immediately.

On the Origin of Species is undoubtedly the most famous book in the history of the life sciences, and one of the world's most famous books on any subject. It is also perhaps the most published book in the history of science and the most translated book originally published in English. As a result of this fame, a great deal of historical research has been concentrated on this work. Early in 2009 Cambridge University Press published The Cambridge Companion to the "Origin of Species," edited by Michael Ruse and Robert J. Richards. Most pertinent to book collecting and book history is the excellent chapter on "The Origin of Species as a Book" by Michèle Kohler and Chris Kohler.

Among the many very informative details the Kohlers include, of particular interest to the history of collecting rare books in the history of science is their observation that the first edition may have first been offered as collectable "rare book" by Bernard Quaritch Ltd in 1903 for £2-10-0, "a premium on the price of a new copy, not a discount." (p. 345). They also observe that the price of the first edition remained essentially static in the rare book trade until it began to rise in the 1920s, after which it very gradually moved upward. When I first opened my shop at the beginning of 1971 the price of a fine copy of the first edition in the original cloth was $1000. At this time the work was relatively common, and there were usually several copies of the first edition on the market at one time. In 2014 a fine copy of the first edition was worth approximately $150,000. This represented an appreciation rate far higher than most other science classics.

♦ In 2014 darwin-onlin.org.uk made available Darwin's complete publications, his private papers and manuscripts, and so-called "supplementary works." When I visited the site its index page advertised,"over 400 million hits since 2006."  Another site, the Darwin Manuscripts Project at the American Museum of Natural History in New York, provided DARBASE, a union catalogue of Darwin manuscripts in institutions and private collections.  An intriguing brief manuscript in Darwin's hand reproduced there showed that Darwin apparently considered writing a chapter "On the Geological Antiquity of Man And on the Descent (origin) of Species by variation." This was a topic of interest to me in 2014 as we prepared our book on The Discovery of Human Origins. My research till 2014 indicated that Darwin avoided publishing on the topic of human origins, leaving it to Huxley, Lyell and others. 

According to their children's accounts, Charles and Emma Darwin and their children had a happy family life, and Darwin was known not to be protective of his manuscripts after they were published. As a result, the Darwin children were allowed to doodle on the versos of some of his manuscripts, including the original manuscript of On the Origin of Species. In February 2014 reproductions of some of the more elaborate of those doodles were reproduced at this link.

Hook & Norman, The Haskell F. Norman Library of Science and Medicine (1991) No. 593.

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Hemoglobin is Named 1864

In 1864 German physiologist and chemist in Tübingen Felix Hoppe-Seyler named the protein crystallized from blood haematoglobulin or haemoglobin (hemoglobin).

Hoppe-Seyler, “Ueber die chemischen und optischen Eigenschaftern des Blutsfarbstoffs,Arch. f. path. Anat. u. Physiol. (Virchow’s Archiv) 29 (1864) 233-35.

Judson, Eighth Day of Creation, 490.

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Mendel's Discovery of the Mendelian Ratios 1866

Augustinian Abbey of St. Thomas in Brno

Gregor Mendel

In 1866 Austrian scientist and friar of the Augustinian Abbey of St Thomas in Brno (now Czech Republic) Gregor Mendel published "Versuche ber Pflanzen-Hybriden," Verhandlungen des naturforscheden Vereines in Brünn 4 1865, [3]-47 (1866). Reporting Mendel's eight years of experimental work on artificial plant hybridization, this paper recorded the discovery of the Mendelian ratios, the most significant single achievement in the history of genetics. Working with clearly identifiable traits in the pea plant, (seed color and shape, stem length, position of the flowers) Gregor Mendel discovered a generalized set of rules concerning heredity. He postulated that there are discrete units of heredity (what we call genes) that are transmitted from generation to generation even though some of these are not expressed as an observable trait in every generation. He discovered dominant and recessive traits— what we call segregation and what we call alleles

"In comparison with his predecessors, Mendel was original in his approach, and in his interpretation of experimental results. He reduced the hitherto extremely complex problem of crossing and heredity to an elementary level appropriate to exact analysis. He left nothing to chance. . . . Altogether new was his use of large populations of experimental plants, which allowed him to express his experimental results in numbers and subject them to mathematical treatment. By the statistical analysis of large numbers Mendel succeeded in extracting "laws" from seemingly random phenomena. This method, quite common today, was then entirely novel. Mendel, inspired by physical sciences, was the first to apply it to the solution of a basic biological problem and to explain the significance of a numerical ratio" (D.S.B.).

Published in the obscure journal of a provincial natural science society, Mendel's work went virtually unnoticed, and remained so until 1900 when the Mendelian ratios were independently rediscovered by Hugo de Vries, Carl Correns and Erich von Tschermak.

♦ In February 2012 Mendel's original manuscript of his famous paper was returned to the Mendel Museum at the Augustinian Abbey of St. Thomas in Brno. The monastery had been closed down in 1953 at which time the manuscript was hidden by the Augustinian monks. In the 1980s the manuscript was sent for safekeeping to Vienna, and then to Germany.  After much negotiation between the Czech Republic and Germany the manuscript was returned to the place of its origin.

Dibner, Heralds of Science no. 35. Norman, Morton's Medical Bibliography (1991) no. 222. Horblit, One Hundred Books Famous in Science no. 73a.  Carter & Muir, Printing and the Mind of Man (1967) no. 356.  Hook & Norman, The Haskell F. Norman Library of Science and Medicine (1991) no. 1490.

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Johannes Friedrich Miescher Discovers DNA 1869 – 1871

Felix Hoppe Seyler

University of Tübingen

Friedrich Miescher

In 1869, while working at Felix Hoppe-Seyler's laboratory at the University of Tübingen, Germany, Swiss physician and biologist Johannes Friedrich Miescher  isolated a new class of compounds rich in organic phosphorous from the nuclei of white blood cells. These he called nuclein (nuclear protein). In 1871 Miescher published this discovery in "Ueber die chemische Zusammensetzung der Eiterzellen,"  Hoppe-Seyler, Felix, ed., Med.-chem. Untersuchungen , IV (1866-71) 441-60. Miescher concluded correctly that these "nucleins," were as important a center of metabolic activity as the proteins.

Miescher’s “nuclein” was later demonstrated to be the hereditary genetic material (DNA). He also was the first to suggest the existence of a genetic code.

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1875 – 1900

Discovery of Mitosis 1878 – 1882

In 1878 German biologist and founder of cytogenetics Walther Flemming at the University of Kiel published the results of his investigations of the process of cell division and the distribution of chromosomes to the daughter nuclei, a process he called mitosis from the Greek word for thread. His researches were first published in "Zur Kenntniss der Zelle und ihrer Theilungs-Erscheinungen," Schriften des Naturwissenschaftlichen Vereins für Schleswig-Holstein 3 (1878) 23–27. Continuing his researches, he published further results in 1882 Zellsubstanz, Kern und Zelltheilung (Cell Substance, Nucleus and Cell Division), a work which contained over 100 drawings. On the basis of his discoveries, Flemming surmised for the first time that all cell nuclei came from another predecessor nucleus; he coined the phrase omnis nucleus e nucleo, after Rudolph  Virchow's phrase omnis cellula e cellula.

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Suggesting that the Nucleus Contains the Material Basis of Heredity 1883

Wilhelm Roux

A diagram of mitosis

In Über die Bedeutung der Kerntheilungsfiguren (Leipzig, 1883) German zoologist and embryologist Wilhelm Roux presented the report of his investigation why the nucleus undergoes the precise division of mitosis while the rest of the cell undergoes a rather crude division when one cell splits into two. He argued that mitosis ensures a precise halving of the nucleus, suggesting that the nucleus contains the material basis of heredity.

J. Norman (ed) Morton's Medical Bibliography (1991) no. 229.

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Isolation of Nucleic Acid & Naming its Five Constituent Organic Compounds 1886 – 1901

In "Zur Chemie des Zellkerns," Hoppe-Seyl. z. physiol. Chem. 7 (1882-83) 7-22; 10 (1886) 248-64; 22 (1896-97) 176-87, German biochemist Albrecht Kossel of Berlin showed that the substance called "nuclein" consisted of a protein component and a non-protein component. Kossel further isolated and described the non-protein component. This substance has become known as nucleic acid, which contains the genetic information found in all living cells.

Between 1885 and 1901, Kossel isolated and named the five constituent organic compounds of nucleic acid: adeninecytosineguaninethymine, and uracil. Now known collectively as nucleobases, these compounds provide the molecular structure necessary in the formation of stable DNA and RNA molecules.

Kossel, "Ueber die Nucleinsäure," Arch. Anat. Physiol., Physiol. Abt., (1893) 157-64; (1894) 194-203.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) nos. 702, 719.

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Decisive Proof of Chromosomal Individuality 1888

Theodor Boveri

Human chromosomes

Diagram of a centrosome

In "Zellen-Studien", Jena Z. Naturw., 22 (1888) 685-882, German biologist Theodor Boveri presented decisive proof of the maintenance of chromosomal individuality. Boveri's work with sea urchins showed that it was necessary to have all chromosomes present in order for proper embryonic development to take place. This discovery was an important part of the Boveri–Sutton chromosome theory. His other significant discovery was the centrosome, which he first described and named in this paper.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) 231.1.

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Postulating that Inheritance of Specific Traits is Controlled by Particles Called Pangenes 1889 – 1909

Hugo de Vries

Wilhelm Johannsen

In 1889 Dutch botanist and geneticist Hugo de Vries published Intracellulare Pangenesis in Jena at the press of Gustav Fischer. In this brief book he postulated that inheritance of specific discrete traits was transmitted during cell division by particles which he called pangens (English: pangenes). These he described as the smallest particle representing one hereditary characteristic. 

♦ Twenty years later Danish botanist and geneticist Wilhelm Johannsen abbreviated de Vries's term to gen to describe the fundamental physical and functional units of heredity. "Gen" in Danish and German word was translated into English as "gene."

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The Weissmann Barrier 1892

August Weismann

In 1892 German physician, zoologist and evolutionary biologist August Weismann, of Freiburg im Breisgau, published two books providing experimental evidence that acquired characteristics were not inherited. Aufsätze über Vererbung und verwandte biologische fragen and Das Keimplasma. Eine Theorie der Verebung.

According to Weissman's germ plasm theory, in a multicellular organism inheritance only takes place by means of the germ cellsgametes such as egg cells and sperm cells. Other cells of the body, somatic cells, do not function as agents of heredity. The effect is one-way: germ cells produce somatic cells and are not affected by anything the somatic cells learn, or any ability the body acquires during its life. Therefore genetic information cannot pass from soma to germ plasm and on to the next generation. This is referred to as the Weismann barrier.

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Discontinuous Variation as a Source of Evolutionary Change 1894

William Bateson

In 1894 English geneticist and Fellow of St. John's College, Cambridge, William Bateson published Materials for the Study of Variation Treated with Especial Regard to Discontinuity. This was Bateson's major work before his rediscovery of Mendel's laws of heredity. Like many other scientists during the last decades of the 19th century, Bateson rejected the orthodox Darwinian doctrine of natural selection, which taught that evolutionary change was the result of gradual and continuous accretion of seemingly insignificant variations. Bateson emphasized the importance of major or discontinuous variation as the source of evolutionary change, studying plant hybrids in an effort to determine how discontinuous variations are inherited, and summarizing his discoveries in the Materials.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 237.

Hook & Norman, The Haskell F. Norman Library of Science & Medicine (1991) no. 134. 

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"The Enzyme and Substrate Must Fit Each Other Like a Lock and a Key" 1894

In his paper "Einfluss der Configuration auf die Wirkung der Enzyme," Berichte der deutschen chemischen Gesellschaft 27 (1894) 2985-2993, German chemist Emil Fischer at the University of Berlin provided a structural interpretation of the selectivity of enzymes—their ability to discriminate among very similar molecules, confirming Pasteur's observations in fermentation of tartaric acid. Fischer wrote, “Only with a similar geometrical structure can molecules approach each other closely, and thus initiate a chemical reaction. To use a picture, I should say that the enzyme and substrate must fit each other like a lock and key.” (Quoted by Lesk, Protein Structure, 36).

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Galton's "Law of Ancestral Heredity" 1897

Francis Galton

In his paper "The average contribution of each several ancestor to the total heritage of the offspring," published in the Proceedings of the Royal Society 61 (1897) 401-413, English polymath Francis Galton published his “Law of Ancestral Heredity,” based on both human and basset hound pedigrees. Galton first proposed the law in 1876, and revised it several times over the next two decades. His basic conception was that on average, parents provide offspring with half of inherited traits, grandparents contribute one quarter, great grandparents one eighth, and so on.

"The "law of ancestral heredity," as it turned out, was mistaken. Although he was interested in individual variations, Galton's mathematical methods treated them as "errors." In Gregor Mendel's more carefully conceived experiments with culinary peas, variations represented the expression of discrete alternative factors or (as we would say today) genes. Galton, in his personal correspondence with Darwin, came close to this conception, but never proceeded to a testable formulation." (http://www.genomenewsnetwork.org/resources/timeline/1876_Galton.php,)

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 239.

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Prediction of the Polypeptide Nature of the Protein Molecule 1898

In his paper "Ueber die Eiweissstoffe,” Dtsch. med. Wschr. 24 (1898) 581-82 and later papers German biochemist Albrecht Kossel of Berlin forecast the polypeptide nature of the protein molecule. He proposed “that amino acids and their spatial arrangement with the protein must become the chemical key to understanding of proteins” (Tanford & Reynolds, Nature's Robots, 52). 

J. Norman (ed) Morton's Medical Bibliography (1991) no. 721.

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1900 – 1910

Rediscovery and Confirmation of Mendel's Laws Simultaneously by Three Scientists 1900

Hugo de Vries

Carl Correns

Erich Tschermak, Elder von Seysenegg

In 1900 three scientists independently rediscovered Mendel's laws or ratios, which had remained unnoticed by the scientific community since Mendel had originally published them in 1866. Both de Vries and Correns rediscovered the laws before reading Mendel's paper.

Dutch botanist and geneticist Hugo de Vries published his account of the rediscovery in two papers: 

"Sur la loi de disjonction des hybrides," Comptes rendus Academie des Sciences (Paris) 130 (1900) 845-47.

His more detailed paper was "Das Spaltungsgestetz der Bastarde," Berichte der Deutsche Botanischen
Gesellschaft 18 (1900) 83-90.

Reading de Vries's paper in German led German botanist and geneticist Carl Correns of the University of Tübingen to write his own paper, although Correns claimed he had previously and independently arrived at the same conclusions. Correns's paper was:

"G. Mendel's Regel über das Verhalten der Nachkommenschaft der Rassenbastarde," Berichte der Deutsche Botanischen
Gesellschaft 18 (1900) 158-67.

The third scientist to "rediscover" Mendel's laws was the Austrian agronomist Erich Tschermak, Edler von Seysenegg (Erich von Tschermak).  Tschermak's first paper on the subject was:

"Über künstsliche Kreuzung bei Pisum sativum," Berichte der Deutsche Botanischen Gessellschaft 18 (1900) 232-39. 

His more detailed paper was "Über künstliche Kreuzung von Pisum sativum," Z. landwirsch. Versuchsw. in Osterreich," 3 (1900) 465-555.

Along with de Vries and Correns, Tschermak brought Mendel's work into prominence and confirmed it, though it is thought that Tschermak may not have fully understood the Mendelian laws before he read Mendel's work.

♦ Rediscovery of Mendel's laws clarified inheritance, but Mendel worked with traits of whole organisms (plants).  How characteristics are sorted and combined on a cellular level where reproduction takes place became the research projects of 20th century scientists.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) nos. 239.01, 239.1, 239.2.

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Coining the Term "Genetics" 1900 – 1902

William Bateson

Wilhelm Johannsen

A cover of The Journal of Genetics

Reginald Punnett

In 1900, very soon after Mendel's laws were rediscovered by De Vries, Correns, and Tschermak, the Royal Horticultural Society of England published an English translation of Mendel's 1866 paper as "Experiments in Plant-Hybridisation" in the Journal of the Royal Horticultural Society. Two years later, in 1902, English geneticist and Fellow of St. John's College, Cambridge, William Bateson issued Mendel's Principles of Heredity: a Defense as a small book in a small edition from Cambridge University Press, reprinting 1900 translation together with the first English translation of Mendel's second paper on Hieracium (1869). Bateson's book was the first English textbook on genetics, though the word did not yet exist; Bateson named the science "genetics: in 1905-6. 

Bateson became the chief popularizer of the ideas of Mendel following their rediscovery. In 1909 he published a much-expanded version of his 1902 textbook entitled Mendel's Principles of Heredity. This book, which underwent several printings, was the primary means by which Mendel's work became widely known to readers of English.

"Bateson first suggested using the word "genetics" (from the Greek gennō, γεννώ; "to give birth") to describe the study of inheritance and the science of variation in a personal letter to Alan Sedgwick... dated April 18, 1905. Bateson first used the term genetics publicly at the Third International Conference on Plant Hybridization in London in 1906. This was three years before Wilhelm Johannsen used the word "gene" to describe the units of hereditary information. De Vries had introduced the word "pangene" for the same concept already in 1889, and etymologically the word genetics has parallels with Darwin's concept of pangenesis.

"Bateson co-discovered genetic linkage with Reginald Punnett, and he and Punnett founded the Journal of Genetics in 1910. Bateson also coined the term "epistasis" to describe the genetic interaction of two independent traits" (Wikipedia article William Bateson, accessed 12-16-2013).

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Mutation Theory is Expounded 1901 – 1903

A painting of Hugo de Vries in his retirement, by Thérèse Schwartze

Oenothera

In 1886 Dutch botanist and geneticist Hugo de Vries began studying and experimenting with Oenothera lamarckiana, a species of evening primrose, after discovering a number of variants of this species growing wild in a meadow. Taking seeds from these, and growing them in his experimental gardens, he found that over the years several new forms appeared, most of which bred true.  De Vries called these new forms “mutations” and formulated a series of theses—the Laws of Mutation—in which he postulated that new elementary species arose through a process of discrete steps (“mutations” or “saltations”), and usually remained constant from their moment of origin. The results of his more than ten years of experimentation and study he published in Die Mutationstheorie. Versuche un Beobachtungen über die Entsehung von Arten im Pflanzenreich (2 vols., Leipzig, 1901-1903), in which he described in detail his work on the segregation laws, on phenomena of variation, and on plant mutations as the basis of evolution. 

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 240.   

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Proof that Different Chromosomes Perform Different Functions in Development 1902

Theodor Boveri

In his paper "Über mehrpolige Mitosen als Mittel zur Analyse des Zelkerns," Verhandlungen der physicalisch-medizinischen Gesselschaft zu Würzburg. Neu Folge 35, 67-90 (1902) 67-90, German biologist Theodor Boveri described experiments involving multipolar mitoses in sea urchin eggs feritized by two sperm. The experiments showed that different chromosomes perform different functions in development, and a full complement of chromosomes is necessary for reproduction.

"In culture, fertilized sea-urchin eggs undergo a complex cell division to form four cells without passing through the normal two-cell stage. This cell division involves four distinct spindle poles and the resulting cells, if gently separated, all have the potential to develop into normal adults. Occasionally, eggs will be fertilized simultaneously by two sperm, and in this case cell division also produces four cells or, more rarely, three. By comparing two populations of fertilized eggs, one exposed to a high concentration of sperm and the other to a low concentration, Boveri saw a direct correlation between the number of resulting deformed embryos and the amount of dispermic eggs.

"Boveri then looked at the development of the individual cells from dispermic eggs when separated at the four-cell stage. Unlike the conventionally fertilized eggs, the individual 'quarter embryos' very rarely developed normally. He also observed that the four separated cells tended to develop differently from each other. Boveri quantified these observations and found that the chance of one of a dispermic egg's quarter embryos developing normally was much greater than that of a dispermic egg as a whole: "certain quarters achieve more separately than all four quarters together".

"The nuclear material of each quarter embryo from dispermic eggs was different, because the chromosomes separated randomly towards the four poles. Boveri hypothesized that each cell needed a full set of chromosomes for normal development. If any chromosomes were missing, the cell would lack 'developmental potential', but duplication of chromosomes would have relatively minor effects, in keeping with Mendel's dominant characters" (http://www.nature.com/celldivision/milestones/full/milestone01.html, accessed 12-16-2013).

J. Norman (ed.) Morton's Medical Bibliography 5th ed (1991) no. 241.1

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The First Proof of Mendelian Heredity in Humans 1902 – 1908

In 1908 English physician Archibald Garrod delivered the Croonian Lectures at the Royal College of Physicians in London on inborn errors of metabolism. In his studies of the rare disease alkaptonuria, which affects about one in one million people, Garrod noted that over twenty-five percent of the recorded cases were the offspring of first cousins. In 1902 he consulted the pioneer English geneticist William Bateson about whether the disease might be hereditary. In a footnote to the first of his "Reports to the Evolution Committee of the Royal Society" (1902), Bateson noted Garrod's work and suggested that since first cousins are often similar genetically, Garrod's data might be best understood if one assumed alkaptonuria to be caused by a recessive gene:

"In illustration of such a phenomenon we way perhaps venture to refer to the extraordinarily interesting evidence lately collected by Garrod regarding the rare condition known as "Alkaptonuria." In such persons the substance, alkapton, forms a regular constituent of the urine, giving it a deep brown colour which becomes black on exposure. The condition is exceedingly rare, and, though met with in several members of the same families, has only once been known to be directly transmitted front parent to offspring. Recently, however, Garrod has a noticed that no fewer than five families containing alkaptonuric members, more than a quarter of the recorded cases, are the offspring of unions of first cousins. In only two other families is the parentage known, one of these being the case in which the father was alkaptonuric. In the other case the parents were not related. Now there may be other accounts possible, but we note that the mating of first cousins gives exactly the conditions most likely to enable a rare and usually recessive character to show itself. If the bearer of such a gamete mates with individuals not bearing it, the character would hardly ever be seen; but first cousins will frequently be bearers of similar gametes, which may in such unions meet each other, and thus lead to the manifestation of the peculiar recessive characters in the zygote. See A. E. Garrod, 'Trans. Med. Chir. Soc.,' 1899, p. 367, and 'Lancet,' November 30, 1901."

This was the first proof of Mendelian heredity in humans, and the foundation of human biochemical genetics. Garrod recognized alkaptonuria to be a genetic disease and, in his Croonian lectures of 1908, hypothesized that each such biochemical defect, or "inborn error of metabolism," was caused by an interruption or block in a metabolic sequence due to the congenital lack of a particular enzyme. Little notice was taken of Garrod's work at the time, in part because his hypothesis regarding the "one gene-one enzyme" link could not be tested until the late 1930s-early 1940s, notably in the work of Beadle and Tatum (1941).

Garrod's lectures were first published as "The Croonian Lectures on Inborn Errors of Metabolism," Lancet 2 (1908) 1-7, 142-8. 173-9, 214-20. They were published in book form as Inborn Errors of Metabolism (London, 1909). Garrod's first paper on the subject dealt with alkaptonuria (Lancet 2, 1901, 1484-6.)

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) nos. 244.1, 3921.

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Genetic Variability, Phenotype and Genotype 1903

In 1903 the Danish geneticist Wilhelm Johannsen issued Ueber Erblichkeit in Populationen und in reinem LinienThis work, published in Jena by Georg Fischer, provided more support for the Mendelian laws of inheritance by showing that in certain self-fertilizing plants a pure line of descendants can be maintained indefinitely, in which case natural selection is not effective; selection depends upon genetic variability.

In "Om arvelighed i samfund og i rene linier," Oversigt over det Kongelige Danske Videnskabernes Selskabs Forhandlinger, 3 (1903) 247-270, Johannsen coined the terms phenotype and genotype. Johannsen pubished a German translation of this paper in Ueber Erblichkeit....

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Theorizing that Chromosomes Carry the Hereditary Material 1903

In "The Chromosomes in Heredity," Biological Bulletin 4 (1903) 231-51 American geneticist and physician Walter Stanborough Sutton advanced the theory that Mendel's factors were hereditary particles borne by the chromosomes, and that Mendel's laws for his factors were the direct result of the behavior of chromosomes in meiosis. 

Independently of Sutton, German biologist Theodor Boveri proposed a similar view in Ergebnisse über die Konstitution der chromatischen Substanz des Zelkerns (1904), causing the theory to be known as the "Sutton-Boveri theory or the Boveri-Sutton chromosome theory."

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) nos. 242.1, 242.2.

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DNA is Distinguished from RNA 1903

In his paper “Darstellung und Analyse einiger Nucleinsäuren,” Hoppe-Seyl. Z. physiol. Chem. 39 (1903) 4-8, 133-35, 479-83 Lithuanian American biochemist Phoebus Aaron Theodore Levene, working in New York, distinguished between DNA and RNA.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 725.1.

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The Hardy-Weinberg Equilibrium 1908

In 1908 mathematician G. H. Hardy of Cambridge University and general practitioner and obstetrician Wilhelm Weinberg of Stuttgart independently discovered what came to be known as the "Hardy-Weinberg equilibrium (Hardy–Weinberg principle). This 

"states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences. These influences include non-random matingmutationselectiongenetic driftgene flow and meiotic drive. Because one or more of these influences are typically present in real populations, the Hardy–Weinberg principle describes an ideal condition against which the effects of these influences can be analyzed."

"Mendelian genetics were rediscovered in 1900. However, it remained somewhat controversial for several years as it was not then known how it could cause continuous characteristics. Udny Yule (1902) argued against Mendelism because he thought that dominant alleles would increase in the population. The American William E. Castle (1903) showed that without selection, the genotype frequencies would remain stable. Karl Pearson (1903) found one equilibrium position with values of p = q = 0.5. Reginald Punnett, unable to counter Yule's point, introduced the problem to G. H. Hardy, a British mathematician, with whom he played cricket. Hardy was a pure mathematician and held applied mathematics in some contempt; his view of biologists' use of mathematics comes across in his 1908 paper where he describes this as "very simple".

To the Editor of Science: I am reluctant to intrude in a discussion concerning matters of which I have no expert knowledge, and I should have expected the very simple point which I wish to make to have been familiar to biologists. However, some remarks of Mr. Udny Yule, to which Mr. R. C. Punnett has called my attention, suggest that it may still be worth making...
Suppose that Aa is a pair of Mendelian characters, A being dominant, and that in any given generation the number of pure dominants (AA), heterozygotes (Aa), and pure recessives (aa) are as p:2q:r. Finally, suppose that the numbers are fairly large, so that mating may be regarded as random, that the sexes are evenly distributed among the three varieties, and that all are equally fertile. A little mathematics of the multiplication-table type is enough to show that in the next generation the numbers will be as (p+q)2:2(p+q)(q+r):(q+r)2, or as p1:2q1:r1, say.
The interesting question is — in what circumstances will this distribution be the same as that in the generation before? It is easy to see that the condition for this is q2 = pr. And since q12 = p1r1, whatever the values of p, q, and r may be, the distribution will in any case continue unchanged after the second generation

"The principle was thus known as Hardy's law in the English-speaking world until 1943, when Curt Stern pointed out that it had first been formulated independently in 1908 by the German physician Wilhelm WeinbergWilliam Castle in 1903 also derived the ratios for the special case of equal allele frequencies, and it is sometimes (but rarely) called the Hardy–Weinberg–Castle Law" (Wikipedia article on Hardy-Weinberg principle, accessed 12-16-2013).

Hardy, "Mendelian Proportions in a Mixed Population," Science 28 (1908) 49-50.

Weinberg, "Über den Nachweis der Vererbung beim Menschen," Jahr. Ver.f. Vaterland Nat. Würz. 64 (1908) 369-82.

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The First Large-Scale Investigation of Species Differences at the Molecular Level 1909

In 1909 American scientists Edward Tyson Reichert and Amos Peaslee Brown published from the Carnegie Institution (now Carnegie Institution for Science) in Washington, D.C. The Differentiation and Specificity of Corresponding Proteins and other Vital Substances in Relation to Biological Classification and Organic Evolution: The Crystallography of Hemoglobins

This massive work with 100 plates including 600 images, was the first large-scale investigation of species differences at the molecular level.

“In 1909 appeared an extraordinary volume, The Crystallography of Hemoglobins, by Edward Tyson Reichert, a physiologist at the University of Pennsylvania, and Amos Peaslee Brown, a mineralogist there. Reichert had conceived the ambition to plot the evolutionary relationships among species by the divergences among their protein molecules. His essential idea was merely seventy years ahead of the technology: only with the advent of Frederick Sanger’s methods for sequencing amino acids could students of evolution begin to measure the similarities among proteins, and only with Sanger’s means of sequencing nucleotides in DNA, beginning in 1976, could such measurements of genetic similarity begin to be accurate. But Reichert understood the enormous scope for diversity if proteins were large, specific molecules; he settled on crystal forms—and recruited his colleague Brown—as the means to get at degrees of difference, and on hemoglobin as the easily crystallized protein universal among animals. Their book surveyed the nineteenth-century literature of hemoglobin; catalogued crystals of the stuff from a hundred and nine different vertebrate species—Philadelphia had a good zoo—complete with drawings and measurements of the crystal forms; and ended with six hundred large, clear, well-printed photomicrographs of hemoglobin crystals” (Judson, The Eighth Day of Creation, p. 492).

“Physiologist Edward Reichert of the Carnegie Institution of Washington proposed in 1909 that if a definite relationship between differences in proteins and physiological differences between species could be demonstrated, then ‘a fundamental principle of the utmost importance would be established in the explanation of heredity, mutation, the influence of food and environment, the differentiation of sex, and other great problems of biology, normal and pathological.’ Reichert, together with Amos Brown, examined hemoglobin crystals from about two hundred mammalian species, establishing a taxonomy of hemoglobins that paralleled traditional organismic classification. Mammalian visible attributes were thus replaced by the properties hidden in their molecular structures. Specificity therefore served as a probe into evolutionary change . . .” (Kay, Who Wrote the Book of Life, pp. 43-44). 

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The Theory of Polygenic Inheritance 1909 – 1911

In 1909 Swedish botanist Nils Herman Nillson-Ehle, a professor at Lund University, advanced the "multiple factor" theory, or theory of polygenic inheritance, in which a trait is produced from the cumulative effects of more than one gene. Traits that display a continuous distribution, such as height, hair or skin color, are polygenic. The inheritance of polygenic traits does not show the phenotypic ratios characteristic of Mendelian inheritance, though each of the genes contributing to the trait are inherited as described by Mendel. Einvironmental factors may affect polygenic inheritance, thus adding still other contributing factors to the "multiple factor" theory.

Nilsson-Ehle, "Kreuzungsuntersuchungen an Hafer und Weizen," Lunds Univiversitets Årsskrift. N.F. Atd 2, 5, Nr. 2 (1909) 1-122, N.F. Afd. 2, 7 (1911) Nr. 6, 1-84.

♦ Independently of Nilsson-Ehle, in 1910 American plant geneticist Edward Murray East of Harvard University published an essentially identical theory in "A Mendelian Interpretation of Variation that is Apparently Continuous," American Naturalist 44 (1910) 65-82. 

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) nos. 245, 245.1.

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1910 – 1920

Sex-Linked Inheritance; Demonstration that Genes are Carried on Chromosomes 1910

Around 1908 American geneticist Thomas Hunt Morgan of Columbia University started working on the fruit fly Drosophila melanogaster, and with his students mutated Drosophila through physical, chemical, and radiational means. In his "Fly Room" he began cross-breeding experiments to find inherited mutations, but with no significant success for two years. Finally in 1909, a series of heritable mutants appeared, some of which displayed Mendelian inheritance patterns, and in 1910 Morgan noticed a white-eyed mutant male among the red-eyed wild types. When white-eyed flies were bred with a red-eyed female their progeny were all red-eyed. A second generation cross produced white-eyed males—a sex-linked recessive trait, the gene for which Morgan named white. In discovering sex-linked inheritance Morgan was the first to link the inheritance of a specific trait definitively with a particular chromosome, demonstrating that genes are carried on chromosomes.

Morgan, "Sex-Limited Inheritance in Drosophila," Science 32 (1910) 120-22.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 245.2.

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Genetic Recombination is Proposed September 10, 1911

While studying the chromosome theory of heredity in 1911, American geneticist Thomas Hunt Morgan occasionally noticed that "linked" traits would separate. Meanwhile, other traits on the same chromosome showed little detectable linkage. To explain his results Morgan proposed a process of crossing over, or recombination. Specifically, he proposed that the two paired chromosomes could "cross over" to exchange information. Morgan also proposed that Mendelian factors (genes) are arranged in a linear series on chromosomes, "similar to pearls on a string." He hypothetized that the interchange of genetic information broke the linkage between genes. The closer two genes were to one another on a chromosome, he theorized, the greater their chance of being inherited together. Conversely, genes located farther away from one another on the same chromosome were more likely to be separated during recombination. Therefore, Morgan correctly proposed that the strength of linkage between two genes depends upon the distance between the genes on the chromosome

Morgan, "Random segregation versus coupling in Mendelian inheritance," Science 34 (1911) 384.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 245.3.

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Discovery of the Diffraction of X-Rays in Crystals 1912

After Röntgen’s discovery of x-rays in 1895, scientists speculated that the rays were actually composed of very short electromagnetic waves, but this supposition resisted proof, as it was impossible to construct a diffraction grating with intervals small enough to measure the wavelength. In 1912, German physicist Max von Laue, working in Berlin, came up with the idea of sending x-rays through crystals, arguing that the supposed regular structure of their atoms would approximate the intervals of a diffraction grating. Laue’s associate Walter Friedrich, together with student Paul Knipping, began experimenting on April 12, 1912, and found that the irradiation of a copper sulfate crystal with x-rays produced a regular pattern of dark points on a photographic plate placed behind the crystal. Laue’s discovery of the diffraction of x-rays in crystals, which Einstein called one of the most beautiful in physics, earned Laue the 1914 Nobel Prize in physics.

Laue’s discovery was of dual importance: it allowed the subsequent investigation of x-radiation by means of wavelength determination, and it provided the means for the Braggs’ structural analysis of crystals, for which they received the Nobel Prize in 1915. X-ray analysis of crystals, as initially developed by Sir Lawrence Bragg, became the most widely used technique for the investigation of molecular structure, leading to incalculable advances in both inorganic and organic chemistry, as well as molecular biology. After Max Perutz and his student John Kendrew first successfully applied Braggs’ x-ray crystallographic techniques to the study of the structure of proteins, these techniques were employed by hundreds of thousands of researchers around the world.

Laue, Max (1879-1960), Friedrich, Walter (1883-1968) & Knipping, Paul (1883-1935). "Interferenz-Erscheinungen bei Röntgenstrahlen. . . . Eine quantitative Prüfung der Theorie für die Interferenz-Erscheinungen bei Röntgenstrahlen," Sitzungsb. k. Bayer. Akad. Wiss., math.-phys. Klasse (1912) 303-322, 363-373, 5 photographic plates. 

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Discovery of the "Bragg Relation" in Crystallography November 1912 – February 1913

Five months after Max von Laue published his discovery of the defraction of x-rays in crystals, English physicist William Lawrence Bragg, at the age of 22, discovered that the regular pattern of dots produced on a photographic plate by an X-ray beam passing through a crystal could be regarded as a reflection of electromagnetic radiation from planes in a crystal that were especially densely studded with atoms. From this work the younger Bragg derived the “Bragg relation” or Bragg's law (nλ = 2d sin O). This relates the wavelength of the X-ray to the angle at which such a reflection could occur.

“The Diffraction of Short Electromagnetic Waves by a Crystal,” read 11 Nov. 1912 and published in Proceedings of the Cambridge Philosophical Society 17 (14 Feb. 1913) 43-57; W. H. Bragg, “X-rays and Crystals,” Nature 90 (23 Jan. 1913) 572.

Hook & Norman, The Haskell F. Norman Library of Science & Medicine (1991) No. 311.

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Using Cross-Over Data to Construct the First Genetic Map 1913

Soon after American geneticist Thomas Hunt Morgan of Columbia University presented his hypothesis that the strength of linkage between two genes depends upon the distance between the genes on the chromosome, his student Alfred Henry Sturtevant, then a 19-year-old undergraduate, working in Morgan's Fly Room, realized that if frequency of crossing over was related to distance, one could map out the genes on a chromosome. If the farther apart two genes were on a chromosome, the more likely it was that these genes would separate during recombination, Sturtevant recognized that the "proportion of crossovers could be used as an index of the distance between any two factors" (Sturtevant, 1913). Collecting a stack of laboratory data, Sturtevant went home and spent most of the night drawing the first chromosomal linkage map for the genes located on the X chromosome of fruit flies. He showed that the gene for any specific trait was in a fixed location (locus), and in his 1913 paper Sturtevant included the first genetic map with all its genes in the correct position, and also laid out the logic for genetic mapping. His maps proved that genes are arranged in a linear sequence along chromosomes and paved the way for genetic maps of other species besides Drosophila.

Sturtevant, "The Linear Arrangement of Six Sex-Linked Factors in Drosophila, as shown by their mode of Association," Journal of Experimental Zoology 14 (1913) 43-59. 

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 245.4. 

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Discovery of Nondisjunction 1913

In 1913 Calvin Bridges, a genetics student of Thomas Hunt Morgan at Columbia University, discovered nondisjunction (non-disjunction)— the failure of chromosome pairs to separate properly during meiosis stage 1 or stage 2.

Bridges, "Non-Disjunction of the Sex Chromosomes of Drosophila," Journal of Experimental Zoology 15 (1913) 587-606.

Bridges expanded his research into "a masterful Ph.D. thesis"  entitled on "Non-disjunction as Proof of the Chromosome Theory of Heredity," Genetics 1, no. 2 (March 1916) 107-163.

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Discovery of X-Ray Crystallography July 1913

Continuing their research on x-ray crystallography, the father and son team of physicists at Cambridge, William Henry Bragg and William Lawrence Bragg, constructed the first X-ray spectrometer using crystals as gratings, using a known wavelength to determine the distances between atomic planes—and thus the structure—of crystalline substances. By the end of 1913 the Braggs reduced the problem of crystal structure analysis to a standard procedure.

W. H. and W. L. Bragg, “The Reflection of X-rays by Crystals,Proceedings of the Royal Society of London 88A (1 July 1913): 428-30 and 889A (22 Sept. 1913): 246-48.

The Braggs shared the 1915 Nobel Prize for Physics "For their services in the analysis of crystal structure by means of X-ray." They are the only father and son team to share a Nobel Prize. Lawrence Bragg is the youngest Nobel Laureate, having received the award at the age of 25. Nearly forty years later he was the director of the Cavendish Laboratory, Cambridge, when the epochal discovery of the structure of DNA was reported by James D. Watson and Francis Crick in 1953.

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Mendelian Laws are Demonstrated by Observable Events Occurring in Cells 1915

In 1915 American zoologist and geneticist Thomas Hunt Morgan, and his students and co-workers in the Fly Room at Columbia University: Alfred H. Sturtevant, Hermann J. Muller and Calvin B. Bridges published The Mechanism of Mendelian Heredity. Summarizing the research the team had done since 1910, this widely read textbook presented evidence that genes are arranged linearly on chromosomes, and that Mendelian laws are demonstrated by observable events occurring in cells.

"By 1915 Morgan and his co-workers were able to present the locations on a genetic map for 30 distinct genes of the four Drosophila chromosomes" (Brock pp. 14-15)

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Discovery of Bacteriophages: Viruses that Infect Bacteria 1915

In 1915 English bacteriologist Frederick William Twort of the University of London discovered discovered bacteriophages, a type of virus that attacks bacteria (the term bacteriophage was coined by Félix d’Herelle, who in 1917 independently confirmed Twort’s discovery).

The discovery of bacteriophage began an immensely fruitful line of research that produced, among other things, Avery’s demonstration that DNA is the basic material responsible for genetic transformation (1944) and Alfred Hershey and Martha Chase’s “Waring Blender” experiment showing that DNA is the carrier of genetic information in virus reproduction (1952). Much of this work was done by members of the “phage group,” founded in 1940 by Max Delbrück, Salvador Luria and Hershey. The establishment of the group’s annual summer “phage course” at Cold Spring Harbor in 1945 attracted a great number of researchers to the field, one of whom was the young James Watson, who studied with Delbrück at Cal Tech and obtained his Ph.D. in 1950 at Indiana University under Luria. Watson began his scientific career by investigating bacterial viruses, attempting to study the fate of DNA of infecting virus particles.

“The greater number of workers assimilated into the Phage Group through the Cold Spring Harbor course, as well as the easier access to new tools such as radioactive tracers and ultracentrifuges, engendered more rapid progress during the next seven years. In 1952 the fifty or so stalwarts, gathered at the Abbaye de Royaumont near Paris for the first International Phage Symposium, knew by then that the phage DNA is the sole carrier of the hereditary continuity of the virus and that the details uncovered hitherto concerning the physiology and genetics of phage reproduction were to be understood in terms of the structure and function of DNA. In the very next year, the discovery of the Watson-Crick structure of DNA and the proposed mechanism of its replication provided the fundament for that understanding” (Stent, “Introduction: Waiting for the paradox,” in Phage and the Origins of Molecular Biology, ed. J. Cairns, G. Stent and J. Watson [1992], 3-8, quoting from p. 6).

Twort, "An investigation on the nature of ultra-microscopic viruses," The Lancet 2 (1915) 1241-43.

Brock, The Emergence of Bacterial Genetics, 113-14. Judson, The Eighth Day of Creation, 45-46. 

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Coining the Term Bacteriophage 1917

In 1917 French-Canadian microbiologist Félix d’Herelle, working in Paris, discovered a microbe-eating virus that he called “bacteriophage.” d'Herelle made his discovery independently of the work of Frederick Twort, which was published two years earlier, in 1915.

Bacteriophage was the origin of the modern usage “phage.” Incorrectly d’Herelle believed that bacteriophage played a role in immunity and were a potential therapeutic agent. These misconceptions stimulated research on phage.

d’Herelle, “Sur un microbe invisible antagoniste des bacilles dysentériques,” Comptes rendus 165 (1917) 373-75.

In 1921 d'Herelle published an influential book, Le bactériophage. Son rôle dans l'immunité. This was translated into English the following year as The Bacteriophage. Its Rôle in Immunity.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 2572.

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Foundation of Biometrical Genetics 1918

In 1918 English statistician, evolutionary biologist, geneticist and eugenicist Ronald A. Fisher, then of Bradfield College, published "The Correlation Between Relatives on the Supposition of Mendelian Inheritance," Transactions of the Royal Society of Edinburgh 52 (1918) 399-433. This paper reconciled Mendelian genetics with the biometric observations of Karl Pearson and Francis Galton. It laid the foundation for what came to be known as biometrical genetics, introducing the analysis of variance— a considerable advance over the earlier correlation methods, and included the first use of "variance" in statistics. The paper showed that the inheritance of traits measurable by real values (i.e., continuous or dimensional traits) is consistent with Mendelian principles. It formed the basis of the genetics of complex trait inheritance, and mitigated debates between biometricians and Mendelians on the compatibility of particulate inheritance with natural selection

"Fisher had originally submitted his paper (then entitled "The correlation to be expected between relatives on the supposition of Mendelian inheritance") to the Royal Society, to be published in the [Philosophical] Transactions of the Royal Society of London. The two referees, the biologist R. C. Punnett and the statistician Karl Pearson, believed that the paper contained areas they were unable to judge, due to lack of expertise, and expressed some reservations. Though the paper was not rejected, Fisher carried a feud with Pearson from 1917 on, and instead sent the paper via J. Arthur Thomson to the Royal Society of Edinburgh, which published it in its Transactions" (Wikipedia article on The Correlation between Relatives...., accessed 12-21-2013).

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 248. 

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First Use of the Word Gene 1919

In 1919 American geneticist Thomas Hunt Morgan of Columbia University published The Physical Basis of Heredity. In this book he first used the word gene. Previously he had used the term "Mendelian unit"or "factor". 

"On the basis of genetic analysis, Morgan could present a number of characteristics of genes.

1. A gene could have more than one effect. For instance, insects that had the white-eye gene not only had white eyes, but also grew slower and had a lower viability.

2. The effects of the gene could be modified by external conditions, but these modifications were not transmitted to future generations. The gene itself was stable; only the character that the gene controlled varied.

3. Characters that were indistinguishable phenotypically could be the product of different genes.

4. At the same time, each character was the product of many genes. For instance, 50 different genes were known to afect eye color, 15 affected body color, and 10 affected length of wing.

5, Heredity was therefore not some property of the 'organism as a whole', but rather of the genes.

6. Genes of the pair did not ump out of one chromosome into another, but changed when the chromosome thread broke as a piece in front of or else behind them. Thus, crossing-over affected linked genes as groups and was a product of the behavior of the chromosome as an entity.

"Morgan's studies were based, to a great extent, on the availabity of a large number of mutants, bu the nature of the mutation process itself remained a mystery...." (Brock p. 15).

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1920 – 1930

"Mathematical Theory of Natural and Artificial Selection" 1924

With R. A. Fisher and Sewall Wright, British-born geneticist and evolutionary biologist John Burdon Sanderson Haldane (J.B.S. Haldane) developed the mathematical theory of population genetics. In 1924 Haldane began publication of his "Mathematical Theory of Natural and Artificial Selection." The first part appeared in the Transactions of the Cambridge Philosophical Society 23 (1924) 19-41. Parts II through IX appeared in the Proceedings of the Cambridge Philosophical Society from 1924 to 1932. The tenth and final part, "Some Theorems on Natural Selection," appeared in Genetics 19 (1934) 412-429.

In "A Mathematical Theory of Natural and Artificial Selection" Haldane showed the direction and rates of change of gene frequencies. He also pioneered investigation of the interaction of natural selection with mutation and with migration.

In 1932 Haldane issued a book, The Causes of Evolution, summarizing these results for a wider audience, and including the majority of his mathematical treatment of the subject in an extensive appendix. This body of work was a component of what came to be known as the "modern evolutionary synthesis", re-establishing natural selection as the premier mechanism of evolution by explaining it in terms of the mathematical consequences of Mendelian genetics.

In December 2013 when I wrote this entry parts 1 and 10 of Haldane's "Mathematical Theory...." were available at the links provided above, along with part V, which was available at this link. The remaining parts were available to subscribers from the Cambridge Journals website.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 254. 

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Proof that X-Rays Can Induce Mutations 1927

In 1927 American geneticist and educator Herman J. Muller, of the University of Texas at Austin, showed that radiation causes mutations that are passed on from one generation to the next. This was the first suggestion that inherited traits might be altered or controlled, and it created a sensation. “Man’s most precious substance, the hereditary material which he could pass on to his offspring, was now potentially in his control. X rays could  ‘speed up evolution,’ if not in practice at least in the headlines. Like the discoveries of Einstein and Rutherford, Muller’s tampering with a fundamental aspect of nature provoked the public awe “(Carlson, "An unacknowledged founding of molecular biology: H. J. Muller’s Contribution to Gene Theory, 1910-36," Journal of the History of Biology 4 (1971) 149-70). 

A student of Thomas Hunt Morgan, Muller studied mutations and sought to map genes to specific chromosomes, but unlike most other early geneticists, Muller was particularly interested in the physical and chemical nature and operations of genes. Beginning in November 1926 Muller subjected male fruit flies to relatively high doses of radiation, then mated them to virgin female fruit flies. In a few weeks' time he was able to induce more than 100 mutations in the resulting progeny—about half the number of all mutations discovered in Drosophila over the previous fifteen years.

From Muller's work a clear, quantitative connection between radiation and lethal mutations quickly emerged. Some mutations were deadly; the effects of other mutations in offspring were visible but not lethal. As Muller interpreted his results, radioactive particles passing through the chromosomes randomly affected the molecular structure of individual genes, rendering them either inoperative or altering their chemical functions. Muller's discovery created a media sensation after he delivered a paper entitled "The Problem of Genetic Modification" at the Fifth International Congress of Genetics in Berlin. This was published in Verhandlungen des V. Internationalen Kongress fur Veresbungswissenschaft 1927 (1928) 234-260. 

Muller, "Artificial Transmutation of the Gene," Science 66 (1927) 84-87. 

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Demonstration that Bacteria Can Transfer Genetic Information Through an Unidentified Transforming Factor 1928

At the English Ministry of Health's Pathological Laboratory bacteriologist Frederick Griffith was sent pneumococci samples taken from patients throughout the country. He amassed a large number, and would type—in other words classify—each pneumococci sample to research patterns of pneumonia epidemiology. In 1928 he published "The Significance of Pneumococcal Types," Journal of Hygiene (Cambridge) 27 (1928) 113-59. In this paper he showed that Streptococcus pneumoniae, implicated in many cases of lobar pneumonia, could transform from one strain into a different strain. This phenomenon he attributed to an unidentified transforming principle or transforming factor.

Griffith's research was one of the first experiments that suggested that bacteria are capable of transferring genetic information through a process known as transformation. Research by Avery, MacLeod, and McCarty reported in 1944 isolated DNA as the material that communicated this genetic information.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1992) no. 251.2.

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1930 – 1940

R. A. Fisher's "The Genetical Theory of Natural Selection" 1930

The Genetical Theory of Natural Selection published at Oxford in 1930 by English statistician, evolutionary biologist, geneticist, and eugenicist Ronald A. Fisher, developed ideas on sexual selection, mimicry and the evolution of dominance.

"He famously showed that the probability of a mutation increasing the fitness of an organism decreases proportionately with the magnitude of the mutation. He also proved that larger populations carry more variation so that they have a larger chance of survival. It was in this book that he set forth the foundations of what was to become known as population genetics. Fisher's book also had a major influence on the evolutionary biologist W. D. Hamilton and the development of his later theories on the genetic basis for the existence of kin selection.

"Fisher had a long and successful collaboration with E.B. Ford in the field of ecological genetics. The outcome of this work was the general recognition that the force of natural selection was often much stronger than had been appreciated before, and that many ecogenetic situations (such as polymorphism) were not selectively neutral, but were maintained by the force of selection. Fisher was the original author of the idea of heterozygote advantage, which was later found to play a frequent role in genetic polymorphism. The discovery of indisputable cases of natural selection in nature was one of the main strands in the modern evolutionary synthesis" (Wikipedia article on Ronald Fisher, accessed 12-21-2013).

Fisher issued a second, slightly revised edition of the work in 1958. In 1999 The Genetical Theory of Natural Selection. A Complete Variorum Edition edited by Henry Bennett was published by Oxford University Press, reprinting the original 1930 text with footnotes added showing where changes were made in 1958, and with editorial notes and an annotated bibliography of papers by Fisher on topics related to The Genetical Theory of Natural Selection. 

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Wright's Quantitative Theory of the Effects of Natural Selection on Populations 1931

In 1931 American geneticist Sewall Wright at the University of Chicago published "Evolution in Mendelian Populations," Genetics 16 (1931) 97-159. This was the first detailed presentation of Wright's quantitative theory of the effects of mutation, migration, selection, and population size on changes in gene frequencies in populations. Together with R. A. Fisher and J.B.S. Haldane, Wright blended the science of population genetics with Darwin's theory of natural selection to create what was known as the modern evolutionary synthesis.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 253.1.

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"The Inborn Factors in Disease" 1931

In 1931 English physician Archibald Garrod, Regius Professor of Medicine at Oxford, issued The Inborn Factors in Disease from Oxford at the Clarendon Press. The result of his continuing researches on what he previously designated as Inborn Errors of MetabolismGarrod argued that chemical individuality could result in individuals having a predisposition to certain diseases. This concept, which Garrod initially called diathesis, he regarded an an inherited predisposition expressed as chemical individuality in forms more subtle than those so obvious in the inborn errors of metabolism. This view was later much appreciated with the development of recominbant DNA methods to identify inherited genetic defects.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 253.2.

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The First Studies of Proteins by X-Ray Analysis 1931

In 1931 English physicist and molecular biologist at the University of Leeds William Astbury, a student of William Lawrence Bragg, was the first to study proteins by X-ray analysis. He applied X-ray analysis to the structure of hair, wool, and related fibers, of which the protein keratin is the principal component, and identified two states: α-keratin and β-keratin.

"At Leeds Astbury studied the properties of fibrous substances such as keratin and collagen with funding from the textile industry. (Wool is made of keratin.) These substances did not produce sharp patterns of spots like crystals, but the patterns provided physical limits on any proposed structures. In the early 1930s, Astbury showed that there were drastic changes in the diffraction of moist wool or hair fibres as they are stretched significantly (100%). The data suggested that the unstretched fibres had a coiled molecular structure with a characteristic repeat of 5.1 Å (=0.51 nm). Astbury proposed that (1) the unstretched protein molecules formed a helix (which he called the α-form); and (2) the stretching caused the helix to uncoil, forming an extended state (which he called the β-form). Although incorrect in their details, Astbury's models were correct in essence and correspond to modern elements of secondary structure, the α-helix and the β-strand (Astbury's nomenclature was kept), which were developed twenty years later by Linus Pauling and Robert Corey in 1951. Hans Neurath was the first to show that Astbury's models could not be correct in detail, because they involved clashes of atoms. Interestingly, Neurath's paper and Astbury's data inspired H. S. Taylor (1941,1942) and Maurice Huggins (1943) to propose models of keratin that are very close to the modern α-helix.

"In 1931, Astbury was also the first to propose that mainchain-mainchain hydrogen bonds (i.e., hydrogen bonds between the backbone amide groups) contributed to stabilizing protein structures. His initial insight was taken up enthusiastically by several researchers, including Linus Pauling" (Wikipedia article William Astbury, accessed 01-16-2014).

W. T. Astbury and A. Street, "X-ray Studies of the Structures of Hair, Wool, and Related Fibres. I. General," Philosophical Transactions, Series A, 230 (1932), 75-101.

Tanford & Reynolds, Nature's Robots, 80-81. 

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Niels Bohr Asks if Living Processes Could be Described in Terms of Pure Physics and Chemistry 1933

In 1933 Danish physicist Niels Bohr delivered a lecture on Light and Life before an international congress of light therapists in Copenhagen. His lecture marks his first detailed attempt to apply concepts arising from quantum mechanics (particularly complementarity) to areas outside physics.

“Here, for the first time, Bohr raised a question that was to preoccupy him, off and on, until his death: Would it ever be possible to push the analysis of living processes to the limit where they can be described in terms of pure physics and chemistry?” (Pais, Niels Bohr's Times, 411, 441-42, quote from 442).

Bohr’s lecture may be viewed as one of the foundation stones of molecular biology, in that it inspired the young physicist Max Delbrück (who was in the audience when Bohr delivered it) to switch from physics to biology “to find out whether indeed there was anything to this point of view” (quoted in Pais, p. 442). In 1935, two years after hearing Bohr’s lecture, Delbrück and two other scientists published a paper on genetic mutations caused by x-ray irradiation, in which they concluded that the gene must be a molecule. The ideas expressed in that paper inspired Schrödinger to write his famous What is Life?, a work which in turn motivated Watson, Crick, Wilkins and other scientists to devote their careers to unraveling “the secret of the gene” (quoted in Moore, Schrödinger, p. 403). Delbrück himself became a leader of what was known as the “phage group” of bacterial geneticists; in 1969, he received a share of the Nobel Prize for physiology / medicine for describing the means by which living cells are infected with viruses. “It is fair to say that with Max [Delbrück], Bohr found his most influential philosophical disciple outside the domain of physics, in that through Max, Bohr provided one of the intellectual fountainheads for the development of 20th century biology” (quoted in Pais, p. 442).

Bohr's lecture was published in Danish as "Lys og liv," Naturens Verden 17 (1933) 49-59. It was published in English as "Light and Life," Nature 131 (March 25, 1933) 421-423, and it was also published in German.  

Judson, The Eighth Day of Creation, 32-35.

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The Beginning of Protein Crystallography: Possibly the Beginning of Structural Molecular Biology 1934

In 1934 British crystallographer, polymath and writer John Desmond Bernal at the University of London, and British chemist and crystallographer Dorothy Crowfoot (Hodgkin), took the first X-ray photograph of a protein structure—crystalline pepsin. They showed that crystals of pepsin give an X-ray diffaction pattern, beginning protein crystallography. This may also be the beginning of structural molecular biology.

Bernal & Crowfoot, "X-Ray Photographs of Crystalline Pepsin," Nature 133 (1934) 794-95.

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Timofeeff-Ressovsky Publishes One of the Key Conceptual Papers in the Early History of Molecular Biology 1935

In 1935 Soviet biologist and geneticist Nikolai Vladimirovich Timofeeff-Ressovsky (Nikolaj Vladimirovich Timofeev-ResovskijНиколай Владимирович Тимофеев-Ресовский), working in Berlin, in collaboration with German physicist and radiation biologist Karl Zimmer and German-American biophysicist Max Delbrück, published "Ueber die Natur der Genmutation und der Genstruktur," Nachrichten von der Gesellschaft der Wissenschaften zu Göttingen, mathematisch-physikalische Klasse, Fachgruppe VI, 1, (1935), [189]-245. 

One of the key conceptual papers in the early history of molecular biology, this work represented the debut in genetics of the physicist Max Delbrück, a student and lifelong friend of Danish physicist Niels Bohr. Delbruck turned from quantum physics to biology after being inspired by speculations in Bohr's 1932 lecture "Light and life," about the application of quantum mechanics to problems in biology. 

"Über die Natur der Genmutation und der Genstruktur" (often referred to as "the green paper" after the color of its printed wrappers, or the "Dreimanner" paper after the number of its authors) was divided into four sections. The first, by Timofeeff-Ressovsky, described the mutagenic effects of x-rays and gamma rays on Drosophila melanogaster; the second part, by Zimmer, analyzed Timofeeff-Ressovsky's results theoretically. The third and most remarkable section, by Delbrück, put forth a model of genetic mutation based on atomic physics that "shows the maturity, judgment and breadth of knowledge of someone who had been in the field for years . . . its carefully worded predictions have stood the test of time" (Perutz, p. 557).

The three authors of the paper "concluded that a mutation is a molecular rearrangement within a particular molecule, and the gene a union of atoms with which a mutation, in the sense of a molecular rearrangement or dissociation of bonds, can occur. The actual calculations of the size of the gene, deduced from calculations on the assumption of a spherical target, were not cogent, as Delbrück [later] wryly admitted in his Nobel Prize lecture, but the entire approach to the problem of mutation and the gene adopted by the three collaborators was highly stimulating to other investigators" (DSB [suppl.]).

The Timofeeff-Zimmer-Delbrück paper provided much of the material for Erwin Schrodinger's book What is Life? (1944), a work that takes a "naive physicist's" approach to the problems of heredity and variation; it is often cited as having inspired Watson, Crick, Wilkins and others to focus their careers on the problems of molecular biology. In his 1987 paper, "Physics and the Riddle of Life," Max Perutz examined the relationship between Schrodinger's book and the Timofeeff-Zimmer-Delbrück paper, pointing out, among other things, that the two most important chapters in Schrodinger's book were paraphrased from "Ueber die Natur der Genmutation und der Genstruktur."

"In retrospect, the chief merit of What is Life? is its popularization of the Timofeeff, Zimmer and Delbrück paper that would otherwise have remained unknown outside the circles of geneticists and radiation biologists" (Perutz, p. 558). Perutz, "Physics and the riddle of life," Nature 326 (1987) 555-559.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 254.1

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Felix Haurowitz Suggests that Hemoglobin is a Molecular Lung 1938

In 1938, while working at the Charles University in Prague, Czech-American biochemist Felix Haurowitz discovered that crystalline deoxyhemoglobin changes in shape and color on reaction with oxygen, suggesting that it is a molecular lung. Haurowitz, “Das Gleichgewicht zwischen Hämoglobin and Sauerstoff,” Hoppe-Seyl. Z. Physiol. Chem. 254 (1938) 266-72.

To escape the holocaust, in April 1939 Haurowitz and his family emigrated to Turkey, where Haurowitz became Professor and Director of the Institute for Biological and Medical Chemistry in Istanbul. After World War II Haurowitz emigrated to the United States and became professor at Indiana University in Bloomington. There in 1949 James D. Watson took Haurowitz’s course on proteins and nucleic acids.

Max Perutz, Science is Not a Quiet Life, xviii. (Haurowitz was married to one of Perutz's cousins.)

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Warren Weaver Coins the Term "Molecular Biology" 1938

Perhaps the only mathematician to name a new biological discipline, in 1938, as Director of the Natural Sciences Division of the Rockefeller Foundation, Warren Weaver coined the term molecular biology to describe the use of techniques from the physical sciences (X-rays, radioisotopes, ultracentrifuges, mathematics, etc. ) to study living matter. In the same year the Rockefeller Foundation awarded research grants to Linus Pauling for research on the structure of hemoglobin. Under Weaver's direction the Rockefeller Foundation became a primary funder of early research in molecular biology.

Warren Weaver, "Molecular biology: origin of the term", Science 170 (1970) 591-2. 

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Pauling's "The Nature of the Chemical Bond" 1939

In 1939 American chemist Linus Pauling issued his textbook The Nature of the Chemical Bond and the Structure of Molecules and Crystals: An Introduction to Modern Structural Chemistry. This set forth in detail his valence-bond theory based on the quantum-mechanical concept of resonance between two energy states, which led to his highly innovative idea that the hybridization of orbitals (electron waves) between atoms is what makes molecular structure possible. Pauling’s work “taught a couple of generations of chemists that the sizes and electrical charges of atoms determine exactly [emphasis mine] their arrangement in molecules” (Judson, The Eighth Day of Creation, p. 57); in biochemistry, it proved essential to understanding the helical structure of DNA and other complex proteins. Pauling was awarded the Nobel Prize for chemistry in 1954 for his research into the nature of the chemical bond.

"The Nature of the Chemical Bond was written in language that chemists could understand. Pauling purposely left out almost all mathematics and detailed derivations of bonds from quantum mechanics, concentrating instead on description and real-world examples. The book was filled with drawings and diagrams of molecules. It was, considering the breadth of its approach, amazingly readable.

"And it was vitally important. In it Pauling had, as Nobel Laureate Max Perutz later said, shown that "chemistry could be understood rather than being memorized."

"The response to its publication was immediate and enthusiastic. A letter Pauling received from a University of Illinois professor was typical: "I cannot refrain from taking the opportunity to express to you congratulations and my personal appreciation for one of the finest contributions to chemical literature that I have ever read."

"G. N. Lewis, to whom Pauling dedicated the book, wrote him, "I have just returned from a short vacation for which the only books I took were half a dozen detective stories and your ‘Chemical Bond.’ I found yours the most exciting of the lot."

"The book soon became a standard text at most of the nation’s leading universities. It would go through a number of new editions, be translated into French, Japanese, Russian, German and Spanish, and stay in print for almost three decades. It would become a Bible for a new generation of chemists and one of the most cited references in the history of science (http://scarc.library.oregonstate.edu/coll/pauling/bond/narrative/page47.html, accessed 01-16-2014). 

Judson, The Eighth Day of Creation, 51-70. James, Nobel Laureates in Chemistry, 368-78; 422-26. Goertzel & Goertzel, Linus Pauling, 66-77. 

In January 2014 a very comprehensive website on Pauling's work on the nature of the chemical bond, including his classic textbook, was available from Oregon State University at this link.

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1940 – 1950

Fritz Albert Lipmann Discovers the Process by Which Cells Make Available the Energy to Drive Their Manufacturing Processes 1941 – 1945

In 1945 German-American biochemist Fritz Albert Lipmann co-discovered coenzyme A (CoA) and its importance for intermediary metabolism. For this and other research on coenzyme A Lipmann shared the 1953 Nobel Prize in Medicine or Biology with Sir Hans Krebs.  In “Metabolic Generation and Utilization of Phosphate Bond Energy,” Advances in Enzymology 1 (1941) 99-162 illuminated “the process by which cells make available the energy to drive their manufacturing processes” (Judson, Eighth Day of Creation, 246-48, quote from p.  245).

(This entry was last revised on 06-10-2015.)

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The "One Gene- One Enzyme" Hypothesis November 1941

In November 1941 American geneticists at Stanford University George W. Beadle and Edward L. Tatum published the results of their experiments with the bread mold Neurospora crassa. They concluded that ultraviolet light treatment somehow caused a mutation in a gene that controls the synthesis of an enzyme involved in the synthesis of the essential nutrient. They also showed that the defect is inherited in typical Mendelian fashion. 

"...Beadle and Tatum first irradiated a large number of Neurospora, and thereby produced some organisms with mutant genes. They then crossed these potential mutants with non-irradiated Neurospora.

"Normal products of this sexual recombination could multiply in a simple growth medium. However, Beadle and Tatum showed that some of the mutant spores would not replicate without addition of a specific amino acid—arginine. They developed four strains of arginine-dependent Neurospora—each of which, they showed, had lost use of a specific gene that ordinarily facilitates one particular enzyme necessary to the production of arginine" (http://www.genomenewsnetwork.org/resources/timeline/1941_Beadle_Tatum.php, accessed 12-22-2013).

Beadle and Tatum's experiments are often considered the first significant result in what came to be called molecular biology. In 1948 their collaborator at Caltech, Norman Horowitz, characterized their results as the "one gene- one enzyme hypothesis." Although the concept was extremely influential, the hypothesis was recognized as an oversimplification soon after its proposal. More accurately, it was later understood that each gene specifies the production of a single polypeptide— a protein or protein component. Two or more genes may contribute to the synthesis of a particular enzyme, and some products of genes are not enzymes per se, but structural proteins.

Beadle & Tatum, "Genetic Control of Biochemical Reactions in Neurospora," Proceedings National Academy of Sciences 27 (1941) 499-506.

J. Norman, Morton's Medical Bibliography 5th ed (1991) no. 254.3.

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Schrödinger's "What is Life?" "The Program has to Build the Machinery to Execute Itself" March 1943 – 1944

In March 1943 quantum physicist and theoretical biologist Erwin Schrödinger delivered a series of lectures at Trinity College Dublin entitled What is Life? The Physical Aspect of the Living Cell. These lectures popularized ideas about the physical basis of biological phenomena developed by Max Delbrück and N. V. Timofeev-Ressovsky in a paper they published in 1935. Even during wartime in England Schrödinger's lectures gained enough publicity to be reported on in the April 5, 1943 issue of Time magazine. The lectures were published  as a small book in 1944 by Cambridge University Press.  In this form they profoundly influenced James D. Watson and others, such as Francis Crick, whose background was in physics.

Watson wrote: "From the moment I read Schrödinger's What is Life I became polarized toward finding out the secret of the gene" (Watson in Cairns, Phage and the Origins of Molecular Biology, 239).

In his autobiography molecular biologist Sydney Brenner pointed out a fundamental mistake in Schrödinger’s understanding of how genes would operate:

“Anyway, the key point is that Schrödinger says that the chromosomes contain the information to specify the future organism and the means to execute it. I have come to call this ‘Schrödinger’s fundamental error.’ In describing the structure of the chromosome fibre as a code script he states that. ‘The chromosome structures are at the same time instrumental in bringing about the development they foreshadow. They are code law and executive power, or to use another simile, they are the architect’s plan and the builder’s craft in one.’ [Schrödinger, p. 20,]. What Schrödinger is saying here is that the chromosomes not only contain a description of the future organism, but also the means to implement the description, or program, as we might call it. And that is wrong! The chromosomes contain the information to specify the future organism and a description of the means to implement this, but not the means themselves. This logical difference was made crystal clear to me when I read the von Neumann article [Hixon Symposium, 1948] because he very clearly distinguishes between the things that read the program and the program itself. In other words, the program has to build the machinery to execute itself” (Brenner, My Life in Science [2001] 33-34).

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Demonstration that DNA is Responsible for Bacterial Transformation 1944

In 1944 Canadian-born American physician and researcher Oswald T. Avery, Canadian-American geneticist Colin M. McLeod, and American geneticist Maclyn McCarty, at the Rockefeller Institute in New york, published "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. Induction of Transformation by a Desoxyribonucleic [sic] Acid Fraction Isolated from Pneumococcus Type III," Journal of Experimental Medicine 79 (1944) 137-58. The results reported in this paper demonstrated that DNA is the material responsible for bacterial  transformation.

In 1928 English bacteriologist Frederick Griffith demonstrated that Streptococcus pneumoniae, implicated in many cases of lobar pneumonia, could transform from one strain into a different strain. This phenomenon he attributed to an unidentified transforming principle or transforming factor.  In the years that followed a series of Rockefeller researchers, including Oswald Avery, continued to study transformation.

"Though interrupted, sometimes for years at a time, these studies were from 1928 onwards the centerpiece of Avery's lab agenda. Around 1940, they were activated by Colin MacLeod's efforts to purify the chemical agent responsible for changes of serotype — whether proteinnucleic acid, or some other class of molecule — and demonstrate that it was necessary and sufficient to cause the Griffith phenomenon. Studies on pneumococcal transformation were grossly burdened by a wide variety of variables, which needed to be controlled to allow quantitative estimation of transforming activity in extracts undergoing various stages of purification. MacLeod, over a number of years of research, had resolved several thorny technical issues to render the experimental system somewhat more reliable as an assay for biological activity. By the time McCarty arrived at the Rockefeller University, Avery's team had just about decided that the active reagent was not a protein. But what was it then? Could it be a soluble saccharide, RNA, or, least likely, DNA? The progress of this research over the next three years is beautifully described in McCarty's memoirThe Transforming Principle, written in the early 1980s.

"As purification progressed, exposure of extracts to crystalline RNase and to proteinase preparations helped Avery's team determine that the biological activity of extracts was not dependent on RNA or protein. Crystalline DNase was not available until 1948, but biological activity was rapidly reduced by tissue extracts rich in DNase. McCarty's arrival at Rockefeller University was also marked by another milestone, namely, the development of a diphenylamine reagent assay to positively correlate DNA with biological activity. It gradually became evident that the active material in purified extracts had astonishingly high potency in micrograms of DNA that could consummate the pneumococcal transformation in vitro.

"McCarty, MacLeod, and Avery wrestled with the standard of proof required to claim that they had accomplished pneumococcal transformation with highly purified DNA from extracts. After much self-inquiry, in 1944, they published in the Journal of Experimental Medicine that the active material was, indeed, DNA, bereft of protein or any other known polymer" (Wikipedia article on MacLyn McCarty, accessed 12-22-2013).

J. Norman (ed) Morton's Medical Bibliograhy 5th ed (1991) no. 255.3.

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Avery, McLeod & McCarty Discover that Bacteria Share Genetic Information Through Bacterial Conjugation 1946

Inspired by the 1944 Avery, McLeod and McCarty demonstration that that DNA is the material responsible for bacterial  transformation, medical student Joshua Lederberg began to investigate his hypothesis that, contrary to prevailing opinion, bacteria did not simply pass down exact copies of genetic information, making all cells in a lineage essentially clones. After making little progress at Columbia, Lederberg wrote to geneticist Edward Tatum, his post-doctoral mentor, proposing a collaboration. In 1946 Lederberg took a leave of absence to study under Tatum at Yale University. Later that year Lederberg and Tatum showed that the bacterium Escherichia coli entered a sexual phase during which it could share genetic information through bacterial conjugation. In their very brief paper (less than one page) the authors reported the discovery of sexual processes in the reproduction of bacteria: "Gene Recombination in Escherichia coli," Nature 158 (1946) 558. 

J. Norman (ed) Morton's Medical Bibliography (1991) no. 255.4.

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The First Speculation that Amino Acids are Determined by Nucleic Acids July 1946

In July 1946 The Society for Experimental Biology held its first symposium on the topic of Nucleic Acids at Cambridge. At this meeting William Astbury "pointed out "the relationship between the step size of nucleic acid—3.3 angstrom units—and the step size of amino acids—3.5 angstrom units. Astbury discussed the notion of the amino acids being determined by the nucleic acid" (Sydney Brenner, My Life in Science, 30).

Astbury, "X-ray Studies of Nucleic Acids," Symposium Society Experimental Biology 1 (1947) 67-76.

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Sven Furberg First Proposes a Helical Structure for DNA 1948

In 1948 Sven Furberg, a Norwegian scientist working in London at Birkbeck College under J. D. Bernal, conducted researches leading to the first correct determination of the structure of a nucleotide, the main building block of DNA. Furberg was the first to propose a helical structure for DNA and the first to attempt building a model of DNA nucleotides. His original paper models of DNA were pasted into the back of his laboratory notebook, now preserved at the J. Craig Venter Institute.

Furberg's model was "an imaginative synthesis and constructive leap forward in the case of DNA by putting together a model that was single-stranded, eight-fold helix of nucleotides with stacked bases, 3.4Å apart as chemists knew aromatic rings should be, and with puckered five membered sugar rings displaying the conformation he had obtained from his own X-ray crystallographic analysis of cytidine, itself a virtuoso achievement in the late 1940s. Furberg's model was informally well publicized before its formal publication and surely was a striking advance despite being somewhat inaccurate, incomplete and devoid of insight as regards DNA function. The last flaw presumably was the reason that its other promising qualities were ignored even although they could have formed the basis of a further analysis by chemical crystallographers" (Arnott, Kibble & Shallice, "Maurice Hugh Frederick Wilkins," Biographical Memoirs of Fellows of the Royal Society [2006] 464-65).

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Comparing the Functions of Genes to Self-Reproducing Automata September 20, 1948

At the Hixon Symposium in Pasadena, California on September 20, 1948 John von Neumann spoke on The General and Logical Theory of Automata. Within this speech von Neumann compared the functions of genes to self-reproducing automata. This was the first of a series of five works (some posthumous) in which von Neumann attempted to develop a precise mathematical theory allowing comparison of computers and the human brain.

“For instance, it is quite clear that the instruction I is roughly effecting the functions of a gene. It is also clear that the copying mechanism B performs the fundamental act of reproduction, the duplication of the genetic material, which is clearly the fundamental operation in the multiplication of living cells. It is also easy to see how arbitrary alterations of the system E, and in particular of I, can exhibit certain typical traits which appear in connection with mutation, which is lethality as a rule, but with a possibility of continuing reproduction with a modification of traits.” (pp. 30-31).

Molecular biologist Sydney Brenner read this brief discussion of the gene within the context of information in the proceedings of the Hixon Symposium, published in 1951. Later he wrote about in his autobiography:

“The brilliant part of this paper in the Hixon Symposium is his description of what it takes to make a self-reproducing machine. Von Neumann shows that you have to have a mechanism not only of copying the machine, but of copying the information that specifies the machine. So he divided the machine--the automaton as he called it--into three components; the functional part of the automaton, a decoding section which actually takes a tape, reads the instructions and builds the automaton; and a device that takes a copy of this tape and inserts it into the new automaton. . . . I think that because of the cultural differences between most biologists on the one hand, and physicists and mathematicians on the other, it had absolutely no impact at all. Of course I wasn’t smart enough to really see then that this is what DNA and the genetic code was all about. And it is one of the ironies of this entire field that were you to write a history of ideas in the whole of DNA, simply from the documented information as it exists in the literature--that is, a kind of Hegelian history of ideas--you would certainly say that Watson and Crick depended upon von Neumann, because von Neumann essentially tells you how it’s done. But of course no one knew anything about the other. It’s a great paradox to me that in fact this connection was not seen” (Brenner, My Life, 33-36).

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Discovery of the Sex Chromatin: Beginning of Cytogenetics 1949

In 1949 Canadian physician and medical researcher Murray L. Barr and his graduate student Edwart G. Bertram, working at the University of Western Ontario, showed that it is possible to determine the genetic sex of an individual according to whether there is a chromatin mass present on the inner surface of the nuclear membraine of cells with resting or intermittent nuclei (sex chromatin). In Barr's words:

"After several years spent on several research projects, all of which were in the field of neurocytology, i.e. the cells of the nervous system, I decided in 1948 to start a project that was designed to learn whether heightened nerve cell activity produced any structural changes in these cells. The experiment required stimulation of a nerve in cats, during which they were anaesthetized. The animals were anaesthetized again when the portion of the brain containing the stimulated cells was removed for microscopic examination. The cats were therefore subjected to no discomfort or pain.

Just after the details of the experiment had been worked out, Ewart G. Bertram applied for a position as a graduate student leading to the Master of Science degree and we worked together on the project.... Examination of the sections showed that the nerve cell nuclei contained an especially prominent mass of chromatin, i.e. the particulate matter derived from the chromosomes, these being the nuclear components that bear the genes. However, it was soon found that the special mass of chromatin was present in the cell nuclei of some animals and not of others. Checking the experimental records showed that the mass was present in the nuclei of female cats and absent from those of male cats. It was therefore named the sex chromatin because of the sex difference and this discovery was the beginning of the new science of human cytogenetics, i.e. the relation of chromosome abnormalities to developmental defects. Methods of testing suitable for use in humans were devised and before long, it was shown that numerical or structural abnormalities of the chromosome were responsible for a number of developmental defects. The best known are Turner's syndrome in females, Klinefelter's syndrome in males and Down's syndrome in persons of both sexes. The use of testing for chromosomal abnormalities is of particular interest to paediatricians, endocrinologists and psychiatrists, especially those who are involved with the mentally retarded."

Barr & Bertram, "A Morphological Distinction between Neurones of the Male and Female, and the Behaviour of the Nucleolar Satellite during Accelerated Nucleoprotein Synthesis," Nature 163 (4148) (1949) 676-7. doi:10.1038/163676a0.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 255.5

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"The Key to the Whole Double Helix Story" Before Watson & Crick June 1949 – 1952

In June 1949 Norwegian chemist, biologist and crystallographer Sven Furberg, who was first to propose a helical structure for DNA, distributed only about five or six copies of his typed PhD dissertation at Birkbeck College London, entitled An X-ray Study of Some Nucleosides and Nucleotides.

"Furberg, reasoning with marked brilliance and luck from data that were meager but included his own x-ray studies, got right the absolute three-dimensional configuration of the individual nucleotide: where Astbury had set sugar parallel to base, Furberg, in what he called the standard configuration, set them at right angles. As a structural element, that standard configuration was a powerful help. 'Furberg's nucleotide—correcting Astbury's error—was absolutely essential to us,' Crick told me. Furberg went on to draw a couple of models of DNA, one of which was a single chain in helical form with the bases sticking out flat and parallel to each other, rising 3.4 angstroms from one to the next, eight nucleotides making one complete turn of the screw in about 27 angstroms. Plausible physically, this helix had too little in it; it failed to account for the density of DNA. Furberg stopped building models and publishe his results in June of 1949—in his doctoral dissertation. . . .

"Over the next three years, Furberg's results appeared piecemeal in a series of papers. From his thesis, his models were well known to Randall's group at King's College. . . . Otherwise, Furberg's models remained almost unnoticed—even by Bernal, who wrote, in 1968, that they had contained 'the key to the whole double helix story' and blamed himself for 'letting the opportunity slip'; Furberg at last got his helical model into print in Acta Chemica Scandinavica late in 1952, in time for Watson and Crick to cite it in the notes to their announcement of the successful solution the next spring" (Judson, The Eighth Day of Creation, 94).

Furberg, "On the Structure of Nucleic Acids," Acta Chemica Scandinavica (1952) 634-40.

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The Beginning of the Molecular Approach to Disease November 1949

In "Sickle Cell Anemia, a Molecular Disease," Science 110 (1949) 543-48 Linus PaulingHarvey A. ItanoSeymour J. Singer and Ibert C. Wells established sickle-cell anemia as a genetic disease in which affected individuals have a different form of the metalloprotein hemoglobin in their blood. The paper introduced the concept of a "molecular disease," and represents the beginning of molecular medicine.

"The paper helped establish that genes control not just the presence or absence of enzymes (as genetics had shown in the early 1940s) but also the specific structure of protein molecules. It was also an important triumph in the efforts of Pauling and others to apply the instruments and methods of the physical sciences to biology, and Pauling used it promote such research and attract funding" (Wikipedia article on Sickle Cell Anemia, a Molecular Disease, accessed 01-17-2014).

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 3154.1.

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1950 – 1960

"Chargaff's Rules" 1950

In 1950 Austrian-American biochemist Erwin Chargaff of Columbia University reported his observation from analyses of different DNAs that DNA from any cell of all organisms should have a 1:1 ratio of pyrimidine and purine bases and, more specifically, that the amount of guanine is equal to cytosine and the amount of adenine is equal to thymine (base pair equality). Watson and Crick's model of the structure of DNA confirmed Chargaff's Rules.

Chargaff, "Chemical Specifity of Nucleic Acids and the Mechanism of their Enzymatic Degradation," Experimenta (Basel) 6 (1950) 201-9.

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Linus Pauling Reports the First Discovery of a Helical Structure for a Protein February 28, 1951

On his fiftieth birthday, February 28, 1951, American physical chemist Linus Pauling reported with his co-workers at Caltech, the American biochemist Robert Corey and the African-American physicist and chemist Herman Branson, the discovery of the alpha helix (α-helix). This was the first discovery of a helical structure for a protein. Their discovery built upon and confirmed the research of William Astbury reported in 1931.

"Although incorrect in their details, Astbury's models of these forms were correct in essence and correspond to modern elements of secondary structure, the α-helix and the β-strand (Astbury's nomenclature was kept), which were developed by Linus Pauling, Robert Corey and Herman Branson in 1951; that paper showed both right- and left-handed helixes, although in 1960 the crystal structure of myoglobin showed that the right-handed form is the common one. . . .

"Two key developments in the modeling of the modern α-helix were (1) the correct bond geometry, thanks to the crystal structure determinations of amino acids and peptides and Pauling's prediction of planar peptide bonds; and (2) his relinquishing of the assumption of an integral number of residues per turn of the helix. The pivotal moment came in the early spring of 1948, when Pauling caught a cold and went to bed. Being bored, he drew a polypeptide chain of roughly correct dimensions on a strip of paper and folded it into a helix, being careful to maintain the planar peptide bonds. After a few attempts, he produced a model with physically plausible hydrogen bonds. Pauling then worked with Corey and Branson to confirm his model before publication. In 1954 Pauling was awarded his first Nobel Prize "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances" (such as proteins), prominently including the structure of the α-helix" (Wikipedia article on Alpha helix, accessed 01-17-2014).

Pauling, Corey, and Branson, “The Structure of Proteins: Two Hydrogen-Bonded Configurations of the Polypeptide Chain," Proceedings National Academy of Sciences 37 (1951) 205-11.

Judson, The Eighth Day of Creation, 88-89.

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The First Application of an Electronic Computer to Molecular or Structural Biology July 9 – July 12, 1951

At the second English computer conference held in Manchester from July 9-12, 1951 computer scientist John Makepiece Bennett and biochemist and crystallographer John Kendrew described their use of the Cambridge EDSAC for the computation of Fourier syntheses in the calculation of structure factors of the protein molecule myoglobin. This was the first application of an electronic computer to computational biology or structural biology. The first published account of this research appeared in the very scarce Manchester University Computer Conference Proceedings (1951). 

Kendrew and Bennett formally published an extended version of their paper as "The Computation of Fourier Syntheses with a Digital Electric Calculating Machine," Acta Crystallographica 5 (1952) 109-116. 

In 1962 Kendrew received the Nobel Prize in chemistry for his discovery of the 3-dimensional molecular structure of myoglobin, the first protein molecule to be "solved."

Hook & Norman, Origins of Cyberspace (2002) nos. 744 & 745.

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The Hershey-Chase "Waring Blender Experiment" 1952

In the early twentieth century biologists thought that proteins carried genetic information. This was based on the belief that proteins were more complex than DNA. In 1928 Frederick Griffith's research suggested that bacteria are capable of transferring genetic information through a process known as transformation. Research by Avery, MacLeod, and McCarty communicated in 1944 isolated DNA as the material that communicated this genetic information

The Hershey–Chase experiment, often called the "Waring Blender experiment," was conducted in 1952 by American bacteriologist and geneticist Alfred D. Hershey and his research partner American geneticist Martha Chase at Cold Spring Harbor Laboratory, New York. The experiment showed that when bacteriophages, which are composed of DNA and protein, infect bacteria, their DNA enters the host bacterial cell, but most of their protein does not, confirming that DNA is the hereditary material.

Hershey & Chase, "Independent Functions of Viral Protein and Nucleic Acid in Growth of Bacteriophage," J. Gen. Physiol. 36 (1952) 39-56.

Judson, The Eighth Day of Creation, 108. J. Norman (ed) Morton's Medical Bibliography 5th edition (1991) no. 256.

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Rosalind Franklin's Photo #51 of Crystalline DNA May 2 – May 6, 1952

Between May 2 and May 6, 1952 English molecular biologist Rosalind Franklin, working at King's College, Cambridge took photograph No. 51 of the B-form of crystalline DNA. This was her finest photograph of the substance,  showing the characteristic X-shaped "Maltese cross" clearer than before. 

About eight months later, on January 26, 1953, Franklin showed this photograph to physicist and molecular biologist Maurice Wilkins. Four days later, on January 30, 1953 Wilkins showed the photograph to James Watson. 

The following day Watson asked laboratory director Lawrence Bragg if he could order model components from the Cavendish Laboratory machine shop. Bragg agreed. Watson's account of Franklin's photo 51 to Francis Crick confirmed that they had the vital statistics to build a B-form model: the photo confirmed the 20Å diameter, with a 3.4Å distance between bases. This, plus the repeat distance of 34Å, helix slope about 40°, and the likehood of 2 chains, not 3, seemed to be sufficient to build a model.

Franklin's file copy of Photograph 51, labeled in her handwriting, is preserved at the J. Craig Venter Institute.

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The Idea of a Genetic Code 1953 – 1954

In 1953 and 1954 Russian-American theoretical physicist, cosmologist and science writer George Gamow, while at George Washington University, came up with the idea of a genetic code in his paper “Possible Mathematical Relation between Deoxyribonucleic Acids and Proteins” (Det. Kongelige Danske Videnskabernes Selskab: Biologiske Meddeleiser 22, no. 3 [1954] 1-13).

In the fall of 1953 Gamov gave Crick an earlier draft of this paper entitled “Protein synthesis by DNA molecules.”

“Gamov’s scheme was decisive, Crick has often said since, because it forced him, and soon others, to begin to think hard and from a particular slant—that of the coding problem—about the next stage, now that the structure of DNA was known” (Judson,The Eighth Day of Creation, 236).

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Discovery of The Double Helix April 25, 1953

At the Cavendish Laboratory, University of Cambridge, in 1953 James D. Watson and Francis Crick discovered the self-complimentary double-helical structure of the DNA molecule. In their paper, “Molecular Structure of Nucleic Acids. A Structure for Deoxyribose Nucleic Acid,” Nature 171 (1953) 737-38, they stated that, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

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Proposal of a Method of DNA's Method of Replication May 30, 1953

On May 30, 1953 James D. Watson and Francis Crick published “Genetical Implications of the Structure of Deoxyribonucleic Acid, ” Nature 171 (1953) 964-7. In this paper Watson and Crick proposed the the method of replication of DNA. This discovery has been called as significant, or possibly even more significant, than their discovery of the double-helical structure of DNA published in April 1953.

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Crick's "On Protein Synthesis" September 1957

In September 1957 molecular Biologist Francis Crick delivered his paper “On Protein Synthesis,” published in Symp. Soc. Exp. Biol. 12 (1958): 138-63. In it Crick proposed two general principles:

1) The Sequence Hypothesis:

“The order of bases in a portion of DNA represents a code for the amino acid sequence of a specific protein. Each ‘word’ in the code would name a specific amino acid. From the two-dimensional genetic text, written in DNA, are forged the whole diversity of uniquely shaped three-dimensional proteins

"In this context, Crick discussed the 'coding problem'—how the ordered sequence of the four bases in DNA might constitute genes that encode and disburse information directing the manufacture of proteins. Crick hypothesized that, with four bases to DNA and twenty amino acids, the simplest code would involve "triplets"—in which sequences of three bases coded for a single amino acid" (Genome News Network, Genetics and Genomics Timeline 1957).

2) The Central Dogma:

“Information is transmitted from DNA and RNA to proteins but information cannot be transmitted from a protein to DNA.” This paper “permanently altered the logic of biology.” (Judson)

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John Kendrew Reports the First Solution of the Three-Dimensional Molecular Structure of a Protein 1958 – 1960

In 1958 and 1960 molecular biologist John Kendrew published  "A Three-Dimensional Model of the Myoglobin Molecule Obtained by X-ray Analysis" (with G. Bodo, H. M. Dintzis, R. G. Parrish, H. Wyckoff,) Nature 181 (1958) 662-666, and "Structure of Myoglobin: A Three-Dimensional Fourier synthesis at 2 Å Resolution" (with R. E. Dickerson, B. E. Strandberg, R. G. Hart, D. R. Davies, D. C. Phillips, V. C. Shore). Nature 185 (1960) 422-27. These papers reported the first solution of the three-dimensional molecular structure of a protein, for which Kendrew received the 1962 Nobel Prize in chemistry, together with his friend and colleague Max Perutz, who solved the structure of the related and more complex protein, hemoglobin, two years after Kendrew’s achievement. 

Kendrew began his investigation into the structure of myoglobin in 1949, choosing this particular protein because it was “of low molecular weight, easily prepared in quantity, readily crystallized, and not already being studied by X-ray methods elsewhere” (Kendrew, “Myoglobin and the structure of proteins. Nobel Prize Lecture [1962],” pp. 676-677). Protein molecules, which contain, at minimum, thousands of atoms, have enormously convoluted and irregular formations that are extremely difficult to elucidate. In the 1930s J. D. Bernal, Dorothy Hodgkin and Max Perutz performed the earliest crystallographic studies of proteins at Cambridge’s Cavendish Laboratory; however, the intricacies of three-dimensional structure of proteins were too complex for analysis by conventional X-ray crystallography, and the process of calculating the structure factors by slide-rules and electric calculators was far too slow. It was not until the late 1940s, when Kendrew joined the Cavendish Laboratory as a graduate student, that new and more sophisticated tools emerged that could be used to attack the problem. The first of these tools was the technique of isomorphous replacement, developed by Perutz during his own researches on hemoglobin, in which certain atoms in a protein molecule are replaced with heavy atoms. When these modified molecules are subjected to X-ray analysis the heavy atoms provide a frame of reference for comparing diffraction patterns. The second tool was the electronic computer, which Kendrew introduced to computational biology in 1951. The first electronic computer, the ENIAC, which became operational in Philadelphia in 1945, was 10,000 times the speed of a human performing a calculation. In 1951 Cambridge University was one of only three or four places in the world with a high-speed stored-program electronic computer, and Kendrew took full advantage of the speed of Cambridge’s EDSAC computer, and its more powerful successors, to execute the complex mathematical calculations required to solve the structure of myoglobin. Kendrew was the first to apply an electronic computer to the solution of a complex problem in biology.

Nevertheless, even with the EDSAC computer performing the calculations, the research progressed remarkably slowly. Only by the summer of 1957 did Kendrew and his team succeed in creating a three-dimensional map of myoglobin at a resolution the so-called “low resolution”of 6 angstroms; thus myoglobin became “the first protein to be solved” (Judson, p. 538).

“A cursory inspection of the map showed it to consist of a large number of rod-like segments, joined at the ends, and irregularly wandering through the structure; a single dense flattened disk in each molecule; and sundry connected regions of uniform density. These could be identified respectively with polypeptide chains, with the iron atom and its associated porphyrin ring, and with the liquid filling the interstices between neighboring molecules. From the map it was possible to ‘dissect out’ a single protein molecule . . . The most striking features of the molecule were its irregularity and its total lack of symmetry” (Kendrew, “Myoglobin,” p. 681).  

The 6-angstrom resolution was too low to show the molecule’s finer features, but by 1960 Kendrew and his team were able to obtain a map of the molecule at 2-angstrom resolution. “To achieve a resolution of 2 Å it was necessary to determine the phases of nearly 10,000 reflections, and them to compute a Fourier synthesis with the same number of terms . . . the Fourier synthesis itself (excluding preparatory computations of considerable bulk and complexity) required about 12 hours of continuous computation on a very fast machine (EDSAC II)” (Kendrew, “Myoglobin,” p. 682).

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First Proof of the Semiconservative Replication of DNA 1958

The deciphering of the structure of DNA by James Watson and Francis Crick in 1953 suggested that each strand of the double helix would serve as a template for synthesis of a new strand. However, there was no way of knowing how the newly synthesized strands might combine with the template strands to form two double helical DNA molecules. The Meselson–Stahl experiment by American geneticists and molecular biologists Matthew Meselson and Franklin Stahl at Caltech in 1958 supported the hypothesis that DNA replication was semiconservative. In semiconservative replication, each of the two new double-stranded DNA helices consist of one strand from the original helix and one newly synthesized.

Meselson & Stahl, "The Replication of DNA in Escherichia coli," Proceedings National Academy of Sciences 44 (1958) 671-82. 

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 256.6.

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1960 – 1970

Crick & Brenner Propose The Genetic Code 1961

At Cambridge in 1961 Francis Crick, Sydney Brenner and colleagues proposed that DNA code is written in “words” called codons formed of three DNA bases. DNA sequence is built from four different bases, so a total of 64 (4 x 4 x 4) possible codons can be produced. They also proposed that a particular set of RNA molecules subsequently called transfer RNAs (tRNAs) act to “decode” the DNA.

“There was an unfortunate thing at the Cold Spring Harbor Symposium that year. I said, ‘We call this messenger RNA’ Because Mercury was the messenger of the gods, you know. And Erwin Chargaff very quickly stood up in the audience and said he wished to point out that Mercury may have been the messenger of the gods, but he was also the god of thieves. Which said a lot for Chargaff at the time! But I don’t think that we stole anything from anybody— except from nature. I think it’s right to steal from nature, however” (Brenner, My Life, 85).

Francis Crick, L. Barnett, Sydney Brenner and R. J. Watts-Tobin, “General Nature of the Genetic code for Proteins,” Nature 192 (1961): 1227-32.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 256.8.

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Brenner, Jacob & Meselson Demonstrate the Existence of Messenger RNA 1961

In 1961 South African molecular biologist Sydney Brenner working at the Cavendish Laboratory in Cambridge, French molecular biologist François Jacob at the Institut Pasteur in Paris, and American molecular biologist Matthew Meselson at Caltech in Pasadena showed that short-lived RNA molecules that they called messenger RNA (mRNA) carry the genetic instructions from DNA to structures in the cell called ribosomes. They also demonstrated that ribosomes are the site of protein synthesis.

Brenner, Jacob & Meselson, "An Unstable Intermediate Carrying Information from Genes to Ribosomes for Protein Synthesis," Nature 190 (1961) 576-80.

J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) no. 256.10.

In January 2014 images of Sydney Brenner's original autograph manuscript for this paper, and typed drafts were available from the Cold Spring Harbor Laboratories CSHL Archives Repository at this link.

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Jacob & Monod Explain the Basic Process of Regulating Gene Expression in Bacteria 1961

In 1961 French biologists François Jacob and Jacques Monod explained the basic process of regulating gene expression in bacteria, showing that enzyme expression levels in cells is a result of regulation of transcription of DNA sequences. Their experiments and ideas gave impetus to the emerging field of molecular developmental biology, and of transcriptional regulation in particular.

Jacob & Monod, "Genetic Regulatory Mechanisms in the Synthesis of Proteins," Journal of Molecular Biology 3 (1961) 318-56.

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Cyrus Levinthal Builds the First System for Interactive Display of Molecular Structures 1966

In 1966, using the Project MAC, an early time-sharing system at MIT, Cyrus Levinthal built the first system for the interactive display of molecular structures

"This program allowed the study of short-range interaction between atoms and the "online manipulation" of molecular structures. The display terminal (nicknamed Kluge) was a monochrome oscilloscope (figures 1 and 2), showing the structures in wireframe fashion (figures 3 and 4). Three-dimensional effect was achieved by having the structure rotate constantly on the screen. To compensate for any ambiguity as to the actual sense of the rotation, the rate of rotation could be controlled by globe-shaped device on which the user rested his/her hand (an ancestor of today's trackball). Technical details of this system were published in 1968 (Levinthal et al.). What could be the full potential of such a set-up was not completely settled at the time, but there was no doubt that it was paving the way for the future. Thus, this is the conclusion of Cyrus Levinthal's description of the system in Scientific American (p. 52):

It is too early to evaluate the usefulness of the man-computer combination in solving real problems of molecular biology. It does seems likely, however, that only with this combination can the investigator use his "chemical insight" in an effective way. We already know that we can use the computer to build and display models of large molecules and that this procedure can be very useful in helping us to understand how such molecules function. But it may still be a few years before we have learned just how useful it is for the investigator to be able to interact with the computer while the molecular model is being constructed.

"Shortly before his death in 1990, Cyrus Levinthal penned a short biographical account of his early work in molecular graphics. The text of this account can be found here."

In January 2014 two short films produced with the interactive molecular graphics and modeling system devised by Cyrus Levinthal and his collaborators in the mid-1960s was available at this link.

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Max Perutz Solves the Molecular Structure of Hemoglobin at High Resolution 1968

Thirty years after beginning his research on hemoglobin Austrian-born British molecular biologist Max Perutz at Cambridge solved the Fourier synthesis of hemoglobin at 2.8Å, and built an atomic model of the molecule.

Perutz el al, "Three-dimensional Fourier Synthesis of Horse Oxyhaemoglobin at 2.8Å Resolution: The Atomic Model," Nature 219 (1968) 131-39.

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Max Perutz Opens Up the Field of Molecular Pathology August 1968

In August 1968 Max Perutz opened up "the field of 'molecular pathology,' relating a structural abnormality to a disease" (Aaron Klug, "Max Perutz 1914-2002," Science 295 (2002) 2383). Specifically Perutz showed that hemoglobin molecules collapse into a sickle shape in the blood disorder sickle-cell anemia.

Perutz and Lehmann, H., "Molecular Pathology of Human Hemoglobin," Nature 219 (1968) 902-09.

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1970 – 1980

Cohen & Boyer Demonstrate the First Practical Method for Cloning a Gene 1973

In 1973 Stanley Cohen, Annie Chang, Robert Helling, and Herbert Boyer demonstrated that if DNA is fragmented with restriction endonucleases and combined with similarly restricted plasmid DNA, the resulting recombinant DNA molecules are biologically active and can replicate in host bacterial cells. Plasmids can thus act as vectors for the propagation of foreign cloned genes.

This was the first practical method of cloning a gene, and a breakthrough in the development of recombinant DNA technologies and genetic engineering.

Cohen, Chang, Boyer and Helling, “Construction of Biologically Functional Bacterial Plasmids in Vitro,” Proc. Nat. Acad. Sci. 70 (1973): 3240-3244

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The First of the Three Cohen-Boyer Recombinant DNA Cloning Patents is Granted 1974

In 1974 the first of the three Cohen-Boyer recombinant DNA cloning patents was granted, leading to the foundation of the biotechnology industry.

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The Asilomar Conference on Recombinant DNA February 1975

In February 1975 the Asilomar Conference on Recombinant DNA Molecules, organized by Paul Berg, Maxine Singer, and Richard Roblin occurred in Asilomar, California.

"In addition to an international group of 150 scientists, the participants included lawyers (including Daniel Singer, Maxine Singer's husband) to help consider legal and ethical issues, and 16 journalists to cover the four-day event. A primary aim of the group was to consider whether to lift the voluntary moratorium [on recombinant DNA (rDNA) research] and if so, under what conditions research could proceed safely. The participants concluded (though not unanimously) that rDNA research should proceed but under strict guidelines. Their recommendations went to a National Institutes of Health committee chaired by NIH director Donald Fredrickson and charged with formulating those guidelines, which were issued in July 1976" (http://profiles.nlm.nih.gov/CD/Views/Exhibit/narrative/dna.html, accessed 07-25-2009).

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Genentech is Founded April 7, 1976

On April 7, 1976 venture capitalist Robert A. Swanson and biochemist Herbert W. Boyer founded the first genetic engineering company, Genentech, to use recombinant DNA methods to make medically important drugs.

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Gilbert & Maxam Develop a Technique for Sequencing DNA 1977

In 1977 American physicist, biochemist and molecular biologist Walter Gilbert and his student Allan M. Maxam devised a new technique for sequencing DNA. In 1980 Gilbert shared the 1980 Nobel Prize in Chemistry with Frederick Sanger and Paul Berg. Paul Berg received half of the price "for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA". The other half was split between Walter Gilbert and Frederick Sanger "for their contributions concerning the determination of base sequences in nucleic acids"

“The Gilbert-Maxam method involved multiplying, dividing, and carefully fragmenting DNA. A stretch of DNA would be multiplied a millionfold in bacteria. Each strand was radioactively labeled at one end. Nested into four groups, chemical reagents were applied to selectively cleave the DNA strand along its bases--adenine (A), guanine (G), cytosine (C) and thymine (T). Carefully dosed, the reagents would break the DNA into a large number of smaller fragments of varying length. In gel electrophoresis, as a function of DNA’s negative charge, the strands would separate according to length, revealing, via the terminal points of breakage, the position of each base” (http://www.genomenewsnetwork.org/resources/timeline/1977_Gilbert.php, accessed 11-20-2013).

Maxam, A M; Gilbert, W. "A new method for sequencing DNA", Proc. Natl. Acad. Sci. U.S.A. (1977 Feb) 74 (2) 560–4.

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The Sanger Method of Rapid DNA Sequencing 1977

In 1977 English biochemist Frederick Sanger and colleagues at the University of Cambridge independently developed a method for the rapid sequencing of long sections of DNA molecules. Sanger’s method, and that developed by Gilbert and Maxam, made it possible to read the nucleotide sequence for entire genes that run from 1000 to 30,000 bases long. Sanger sequencing was the most widely used sequencing method for approximately 25 years. 

In 1980 Sanger shared the 1980 Nobel Prize in Chemistry with Walter Gilbert and Paul Berg. Paul Berg received half of the price "for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA". The other half was split between Walter Gilbert and Frederick Sanger "for their contributions concerning the determination of base sequences in nucleic acids".  This was Sanger's second Nobel prize.

Sanger, F., Nicklen, S., and Coulson, A.R. "DNA Sequencing with Chain-Terminating Inhibitors," Proc. Nat. Acad. Sci. (USA) 74 (1977) 546-67.

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1980 – 1990

The First Whole Genome Shotgun Sequence 1982

In 1982 British biochemist Frederick Sanger and colleagues sequenced the entire genome of bacteriophage lambda using a random shotgun technique. This was the first whole genome shotgun (WGS) sequence.

Sanger, et alNucleotide Sequence of Bacteriophage Lambda,” J. Mol. Biol. 162 (1982) 729-73.

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The First Study of Ancient DNA (aDNA) November 15, 1984

On November 15, 1984 Russell Higuchi, Barbara Bowman, and Mary Freiberger from the Department of Biochemistry at the University of California, Berkeley and Oliver A. Ryder & Allan C. Wilson, of the Research Department, San Diego Zoo, published "DNA sequences from the quagga, an extinct member of the horse family," Nature 312, 282-284; doi:10.1038/312282a0.  This was probably the first study of DNA isolated from ancient specimens, or ancient DNA (aDNA).

"To determine whether DNA survives and can be recovered from the remains of extinct creatures, we have examined dried muscle from a museum specimen of the quagga, a zebra-like species (Equus quagga) that became extinct in 1883. We report that DNA was extracted from this tissue in amounts approaching 1% of that expected from fresh muscle, and that the DNA was of relatively low molecular weight. Among the many clones obtained from the quagga DNA, two containing pieces of mitochondrial DNA (mtDNA) were sequenced. These sequences, comprising 229 nucleotide pairs, differ by 12 base substitutions from the corresponding sequences of mtDNA from a mountain zebra, an extant member of the genus Equus. The number, nature and locations of the substitutions imply that there has been little or no postmortem modification of the quagga DNA sequences, and that the two species had a common ancestor 3–4 Myr ago, consistent with fossil evidence concerning the age of the genus Equus."

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Origins of the Human Genome Project December 1984 – April 1987

In 1985, as Director of the U.S. Department of Energy’s (DOE) Health and Environmental Research Programs, Charles DeLisi and his advisors proposed, planned and defended before the White House Office of Management and Budget and the Congress, the Human Genome Project. The proposal created a storm of controversy, but was included in President Ronald Reagan’s Fiscal Year 1987 budget submission to the Congress, and subsequently passed both the House and the Senate.

The beginning of the project may have occurred in a workshop known as the Alta Summit held in Alta, Utah, December 1984.

"Robert Sinsheimer, then Chancellor of the University of California, Santa Cruz (UCSC), thought about sequencing the human genome as the core of a fund-raising opportunity in late 1984. He and others convened a group of eminent scientists to discuss the idea in May 1985. This workshop planted the idea, although it did not succeed in attracting money for a genome research institute on the campus of UCSC. Without knowing about the Santa Cruz workshop, Renato Dulbecco of the Salk Institute conceived of sequencing the genome as a tool to understand the genetic origins of cancer. Dulbecco, a Nobel Prize winning molecular biologist, laid out his ideas on Columbus Day, 1985, and subsequently in other public lectures and in a commentary for Science. The commentary, published in March 1986, was the first widely public exposure of the idea and gave impetus to the idea's third independent origin, by then already gathering steam.

"Charles DeLisi, who did not initially know about either the Santa Cruz workshop or Dulbecco's public lectures, conceived of a concerted effort to sequence the human genome under the aegis of the Department of Energy (DOE). DeLisi had worked on mathematical biology at the National Cancer Institute, the largest component of the National Institutes of Health (NIH). How to interpret DNA sequences was one of the problems he had studied, working with the T-10 group at Los Alamos National Laboratory in New Mexico (a group of mathematicians and others interested in applying mathematics and computational techniques to biological questions). In 1985, DeLisi took the reins of DOE's Office of Health and Environmental Research, the program that supported most biology in the Department. The origins of DOE's biology program traced to the Manhattan Project, the World War II program that produced the first atomic bombs with its concern about how radiation caused genetic damage.

"In the fall of 1985, DeLisi was reading a draft government report on technologies to detect inherited mutations, a nagging problem in the study of children to those exposed to the Hiroshima and Nagasaki bombs, when he came up with the idea of a concerted program to sequence the human genome.9 DeLisi was positioned to translate his idea into money and staff. While his was the third public airing of the idea, it was DeLisi's conception and his station in government science administration that launched the genome project" (Robert Mullan Cook-Deegan, Origins of the Human Genome Project, accessed 05-24-2009).

In March 1986 the Department of Energy, Office of Health and Environmental Research, sponsored a workshop at Los Alamos. This was edited by M. Bitensky and published as Sequencing the Human Genome. Summary Report of the  Santa Fe Workshop, March 3-4, 1986

The initial report on the Human Genome Project appeared in April 1987 as:

Report on the Human Genome Initiative for the Office of Health and Environmental Research, Prepared by the Subcommittee on Human Genome of the Health and Environmental Research Advisory Committee for the U.S. Department of Energy Office of Energy Research Office of Health and Environmental Research.

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The First Semi-Automatic DNA Sequencer 1986

In 1986 Leroy Hood and Lloyd Smith from the California Institute of Technology developed the first semi-automatic DNA sequencer, working with a laser that recognized fluorescing DNA markers.

"A biologist at the California Institute of Technology and a founder of API [Applied Biosystems, Inc.], Hood improved the existing Sanger method of enzymatic sequencing, which was becoming the laboratory standard. In this method, DNA to be sequenced is cut apart, and a single strand serves as a template for the synthesis of complementary strands. The nucleotides used to build these strands are randomly mixed with a radioactively labeled and modified nucleotide that terminates the synthesis. Fragments of all different lengths result. The resulting array, sent through a separation gel, reveals the order of the bases. Transferred to film, an "autoradiograph" provides a readable sequence from raw data. This data could be transferred to a computer by a human reader.

"In automating the process, Hood modified both the chemistry and the data-gathering processes. In the sequencing reaction itself, he sought to replace the use of radioactive labels, which were unstable, posed a health hazard, and required separate gels for each of the four DNA bases.

" • In place of radioisotopes, Hood developed chemistry that used fluorescent dyes of different colors—one for each of the four DNA bases. This system of "color-coding" eliminated the need to run several reactions in overlapping gels.

"The fluorescent labels were also aspects of the larger system that revolutionized the end stage of the process—the way in which sequence data was gathered. Hood integrated laser and computer technology, eliminating the tedious process of information-gathering by hand.

" • As the fragments of DNA percolated through the gel, a laser beam stimulated the fluorescent labels, causing them to glow. The light they emitted was picked up by a lens and photomultiplier, and transmitted as digital information directly into a computer" (Genome News Network, Genetics and Genomics Timeline 1989, accessed 05-25-2009).

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1990 – 2000

Expressed Sequence Tags 1991

In 1991 J. Craig Venter and colleagues at the National Institute of Health described a fast new approach to gene discovery using Expressed Sequence Tags (ESTs). Although controversial when first introduced, ESTs were soon widely employed both in public and private sector research. They proved economical and versatile, used not only for rapid identification of new genes, but also for analyzing gene expression, gene families, and possible disease-causing mutations.

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Venter Founds Celera Genomics May 1998

In May 1998 Craig Venter founded Celera Genomics, with Applera Corporation (Applied Biosystems) in Rockville, Maryland, to sequence and assemble the human genome.

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2000 – 2005

The Most Extensive Computation Undertaken in Biology to Date June 26, 2000

The Celera logo

The Human Genome Project logo

On June 26, 2000 "Celera Genomics [Rockville, Maryland] announced the first complete assembly of the human genome. Using whole genome shotgun sequencing, Celera began sequencing in September 1999 and finished in December. Assembly of the 3.12 billion base pairs of DNA, over the next six months, required some 500 million trillion sequence comparisons, and represented the most extensive computation ever undertaken in biology.

The Human Genome Project reported it had finished a “working draft” of the genome, stating that the project had fully sequenced 85 percent of the genome. Five major institutions in the United States and Great Britain performed the bulk of sequencing, together with contributions from institutes in China, France, and Germany” (Genome News Network, Genetics and Genomics Timeline 2000, accessed 05-24-2009).

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IBM Forms a Life Sciences Division August 2000

Reflective of rapid advancements in computational biology and genomics, in August 2000 IBM formed a Life Sciences Solutions division, incorporating its Computational Biology Center.

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Publication of the Human Genome Sequence February 15 – February 16, 2001

Sequencing machine screen shot

"Seven months after the ceremony at the White House marking the completion of the human genome sequence, highlights from two draft sequences and analyses of the data were published in Science and Nature. Scientists at Celera Genomics and the publicly funded Human Genome Project independently found that humans have approximately 30,000 genes that carry within them the instructions for making the body's diverse collection of proteins.

"The findings cast new doubt on the old paradigm that one gene makes one protein. Rather, it appears that one gene can direct the synthesis of many proteins through mechanisms that include 'alternative splicing.' "It seems to be a matter of five or six proteins, on average, from one gene," said Victor A. McKusick of the Johns Hopkins University School of Medicine, who was a co-author of the Science paper.

"The finding that one gene makes many proteins suggests that biomedical research in the future will rely heavily on an integration of genomics and proteomics, the word coined to describe the study of proteins and their biological interactions. Proteins are markers of the early onset of disease, and are vital to prognosis and treatment; most drugs and other therapeutic agents target proteins. A detailed understanding of proteins and the genes from which they come is the next frontier.

"One of the questions raised by the sequencing of the human genome is this: Whose genome is it anyway? The answer turns out to be that it doesn't really matter. As scientists have long suspected, human beings are all very much alike when it comes to our genes. The paper in Science reported that the DNA of human beings is 99.9 percent alike—a powerful statement about the relatedness of all humankind" (Genome News Network, Genetics and Genomics Timeline 2001, accessed 05-24-2009)

References:

Venter, J.C. et al. "The sequence of the human genome," Science 291, 1304-1351 (February 16, 2001).

Lander, E.S. et al. The Genome International Sequencing Consortium. "Initial sequencing and analysis of the human genome," Nature 409, 860-921 (February 15, 2001).

"An initial rough draft of the human genome was available in June 2000 and by February 2001 a working draft had been completed and published followed by the final sequencing mapping of the human genome on April 14, 2003. Although this was reported to be 99% of the human genome with 99.99% accuracy a major quality assessment of the human genome sequence was published in May 27, 2004 indicating over 92% of sampling exceeded 99.99% accuracy which is within the intended goal. Further analyses and papers on the HGP continue to occur. An initial rough draft of the human genome was available in June 2000 and by February 2001 a working draft had been completed and published followed by the final sequencing mapping of the human genome on April 14, 2003. Although this was reported to be 99% of the human genome with 99.99% accuracy a major quality assessment of the human genome sequence was published in May 27, 2004 indicating over 92% of sampling exceeded 99.99% accuracy which is within the intended goal. Further analyses and papers on the HGP continue to occur" (Wikipedia article on Human Genome Project, accessed 01-09-2013).

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2005 – 2010

The Genetic Code of Avian Flu Virus H5N1 is Deciphered October 5, 2005

The Armed Forces Institute of Pathology logo

Colorized transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green)

On October 5,2005 scientists at the Armed Forces Institute of Pathology announced that they deciphered the genetic code of the 1918 avian flu virus H5N1, which killed as many as 50,000,000 people worldwide, from a victim exhumed in 1997 from the Alaskan permafrost. The scientists reconstructed the virus in the laboratory and published the genetic sequence.

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Watson's Genome is Sequenced May 31, 2007

James D. Watson

An example of DNA sequencing

On May 31, 2007 the genome of James D. Watson, co-discoverer of the double-helical structure of DNA, was sequenced and presented to Watson. It was the second individual human genome to be sequenced; the first was that of J. Craig Venter, which was sequenced in the Human Genome Project, the first working draft of which was completed and published in February 2001

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The Cost of DeCoding a Human Genome Drops to $50,000 August 10, 2009

In August 2009 it was announced that bioengineer Stephen R. Quake of Stanford University invented a new technology for decoding DNA that could sequence a human genome at a cost of $50,000. 

"Dr. Quake’s machine, the Heliscope Single Molecule Sequencer, can decode or sequence a human genome in four weeks with a staff of three people. The machine is made by a company he founded, Helicos Biosciences, and costs 'about $1 million, depending on how hard you bargain,' he said.

"Only seven human genomes have been fully sequenced. They are those of J. Craig Venter, a pioneer of DNA decoding; James D. Watson, the co-discoverer of the DNA double helix; two Koreans; a Chinese; a Yoruban; and a leukemia victim. Dr. Quake’s seems to be the eighth full genome, not counting the mosaic of individuals whose genomes were deciphered in the Human Genome Project."

"For many years DNA was sequenced by a method that was developed by Frederick Sanger in 1975 and used to sequence the first human genome in 2003, at a probable cost of at least $500 million. A handful of next-generation sequencing technologies are now being developed and constantly improved each year. Dr. Quake’s technology is a new entry in that horse race.

"Dr. Quake calculates that the most recently sequenced human genome cost $250,000 to decode, and that his machine brings the cost to less than a fifth of that.

“ 'There are four commercial technologies, nothing is static and all the platforms are improving by a factor of two each year,' he said. 'We are about to see the floodgates opened and many human genomes sequenced.'

"He said the much-discussed goal of the $1,000 genome could be attained in two or three years. That is the cost, experts have long predicted, at which genome sequencing could start to become a routine part of medical practice" (Nicholas Wade, NY Times, http://www.nytimes.com/2009/08/11/science, /11gene.html?8dpc).

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2010 – 2012

Construction of the Francis Crick Institute Begins July 2011

In July 2011 construction began for the The Francis Crick Institute (formerly the UK Centre for Medical Research and Innovation), a biomedical research center in London. The Institute is a partnership between Cancer Research UK, Imperial College London, King's College London, the Medical Research Council, University College London (UCL) and the Wellcome Trust. It will be the largest center for biomedical research and innovation in Europe.

The Francis Crick Institute, named after British molecular biologist, biophysicist, and neuroscientist Francis Crick, will be located in a new state-of-the-art 79,000 square meters facility next to St Pancras railway station in the Camden area of Central London. It is expected that researchers will to be able to start work in 2015. Complete cost of the facility is budgeted at approximately £600 million. The institute is expected to employ 1500 people, including 1,250 scientists, with an annual budget of over £100 million. 

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The Cost of Sequencing a Human Genome Drops to $10,500 November 30, 2011

"The cost of sequencing a human genome — all three billion bases of DNA in a set of human chromosomes — plunged to $10,500 last July from $8.9 million in July 2007, according to the National Human Genome Research Institute.  

"That is a decline by a factor of more than 800 over four years. By contrast, computing costs would have dropped by perhaps a factor of four in that time span.  

"The lower cost, along with increasing speed, has led to a huge increase in how much sequencing data is being produced. World capacity is now 13 quadrillion DNA bases a year, an amount that would fill a stack of DVDs two miles high, according to Michael Schatz, assistant professor of quantitative biology at the Cold Spring Harbor Laboratory on Long Island.

"There will probably be 30,000 human genomes sequenced by the end of this year, up from a handful a few years ago, according to the journal Nature. And that number will rise to millions in a few years" (http://www.nytimes.com/2011/12/01/business/dna-sequencing-caught-in-deluge-of-data.html?_r=1&hp, accessed 12-02-2011).

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2012 – 2016

The Cost of Sequencing a Human Genome Drops to $1000 January 10, 2012

On January 10, 2012 Jonathan M. Rothberg, CEO of Guilford, Connecticut-based biotech company Ion Torrent, announced a new tabletop sequencer called the Ion Proton. The company introduced the device at the Consumer Electronics Show in Las Vegas on January 10. At $149,000, the new machine was about three times the price of the Personal Genome Machine, the sequencer that the company debuted about a year ago. But the DNA-reading chip inside it was 1,000 times more powerful, according to Rothberg, allowing the device to sequence an entire human genome in a day for $1,000—a price the biotech industry has been working toward for years because it would bring the cost down to the level of a medical test.

'The technology got better faster than we ever imagined,'Rothberg says. 'We made a lot of progress on the chemistry and software, then developed a new series of chips from a new foundry.' The result is a technology progression that has moved faster than Moore's law, which predicts that microchips will double in power roughly every two years.

"Ion Torrent's semiconductor-based approach for sequencing DNA is unique. Currently, optics-based sequencers, primarily from Illumina, a San Diego-based company, dominate the human genomics field. But, while the optics-based sequencers are generally considered more accurate, these machines cost upwards of $500,000, putting them out of reach for most clinicians. Meanwhile, at Ion Torrent's price, "you can imagine one in every doctor's office," says Richard Gibbs, director of Baylor College of Medicine's human genome sequencing center in Houston, which will be among the first research centers to receive a Proton sequencer.  

"The new Ion Torrent sequencer will also allow researchers to buy a chip that sequences only exons, the regions of the genome that encode proteins. Exons only account for about 5 percent of the human genome, according to the National Human Genome Research Institute, but they are where most disease-causing mutations occur, making so-called exome sequencing a faster and potentially cheaper option for many researchers. Although it's the same price as the genome chip, the Ion Torrent exome chip can sequence two exomes at a time, bringing the per-sequence cost down to $500.  

" 'Some researchers want to sequence single genes, others want to do exomes, and others—for example, cancer researchers—will want to sequence whole genomes, so all three are going to coexist,' says Rothberg. 'It's about finding the right tool for the problem.'  

"Whether Ion Torrent's new technology will be enough to make it the dominant supplier of these tools remains to be seen. A day after the company debuted the Proton sequencer, Illumina also announced that it, too, had reached the $1,000 genome milestone" (http://www.technologyreview.com/biomedicine/39458/?nlid=nldly&nld=2012-01-13, accessed 01-13-2013).

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The First Book Stored in DNA and then Read August 16, 2012

American molecular geneticist George M. Church, director of the U.S. Department of Energy Center on Bioenergy at Harvard & MIT, and director of the National Institutes of Health (NHGRI) Center of Excellence in Genomic Science at Harvard,  Yuan Gao from the Wyss Institute for Biologically Inspired Engineering, and Sriram Kosuri from the Department of Biomedical Engineering, Johns Hopkins University, encoded an entire book into the genetic molecules of DNA, the basic building blocks of life, and then accurately read back the text. Church's book, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves, stored in a laboratory tube, contained 53,426 words, 11 illustrations and a JavaScript program, all of which totalled 5.27 megabits of data. Written with Ed Regis, it was scheduled to be published in printed and electronic editions in October 2012. Church's book was 600 times larger than the largest data set previously encoded in DNA.

"Digital data is traditionally stored as binary code: ones and zeros. Although DNA offers the ability to use four "numbers": A, C, G and T, to minimise errors Church's team decided to stick with binary encoding, with A and C both indicating zero, and G and T representing one.  

"The sequence of the artificial DNA was built up letter by letter using existing methods with the string of As, Cs, Ts and Gs coding for the letters of the book.  

"The team developed a system in which an inkjet printer embeds short fragments of that artificially synthesised DNA onto a glass chip. Each DNA fragment also contains a digital address code that denotes its location within the original file.  

"The fragments on the chip can later be "read" using standard techniques of the sort used to decipher the sequence of ancient DNA found in archeological material. A computer can then reassemble the original file in the right order using the address codes.  

"The book – an HTML draft of a volume co-authored by the team leader – was written to the DNA with images embedded to demonstrate the storage medium's versatility.  

"DNA is such a dense storage system because it is three-dimensional. Other advanced storage media, including experimental ones such as positioning individual atoms on a surface, are essentially confined to two dimensions" (http://www.guardian.co.uk/science/2012/aug/16/book-written-dna-code?INTCMP=SRCH, accessed 09-09-2012).

Church, Gao, Kosuri, "Next-Generation Digital Information Storage in DNA," Science, August 16, 2012: DOI: 10.1126/science.1226355

♦ When the physical book edition of the Church and Regis book was published by Basic Books in October 2012 I acquired a copy. On pp. 269-272 the printed book contained an unusual "afterward", apparently written by Church, entitled "Notes: On Encoding This Book into DNA."  This discussed "some of the legal, policy, biosafety, and other issues and opportunities" pertaining to the process.  The ideas discussed were so distinctive and original that I would have liked to quote it in its entirety but that would have been an infringement of copyright. The section ended with the following statement:

"For more information, and to explore the possibility of getting your own DNA copy of this book, please visit http://periodicplayground.com."  

When I visited the site on October 20, 2012 I viewed a message from networksolutions.com that the site was "under construction."

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The Human Genome is Packed with At Least 4,000,000 Gene Switches September 6, 2012

On September 6, 2012 ENCODE, the Encyclopedia Of DNA Elements, a project of The National Human Genome Research Institute (NHGRI) of the National Institutes of Health, involving 442 scientists from 32 laboratories around the world, published  six papers in the journal Nature and in 24 papers in Genome Research and Genome Biology.

Among the overall results of the project to date was the monumental conclusion that:

"The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as “junk” but that turn out to play critical roles in controlling how cells, organs and other tissues behave. The discovery, considered a major medical and scientific breakthrough, has enormous implications for human health because many complex diseases appear to be caused by tiny changes in hundreds of gene switches" (http://www.nytimes.com/2012/09/06/science/far-from-junk-dna-dark-matter-proves-crucial-to-health.html?pagewanted=all, accessed 09-09-2012).

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The U.S. Supreme Court Rules that Genes Cannot be Patented June 13, 2013

On June 13, 2013 the US Supreme Court in Association for Molecular Pathology et al v. Myriad Genetics, unanimously struck down the patents held by Myriad Genetics of Salt Lake City, Utah, on the DNA comprising BRCA1 and BRCA2. In their abnormal forms these two genes dispose women to a dramatically heightened risk of breast and/or ovarian cancer.  Myriad Genetics had located the two genes, extracted them from the chromosomes housing them, and had obtained the patents on the genes once they were isolated from the human body. 

"The patents controlled by Myriad entitled the company to exclude all others from using the isolated DNA in breast cancer research, diagnostics, and treatment. The plaintiffs—who originally included biomedical scientists and clinicians, advocates for women’s health, and several women with or at risk for breast cancer—held that Myriad’s enforcement of its patents interfered with the progress of science and the delivery of medical services. They contended that genes, even if isolated, were legally ineligible for patents and that well-established tenets of patent law precluded the grant to any person or institution of a monopoly over a substance so essential to life, health, and science as human DNA" (Kevles, Daniel J. "The Genes you Can't Patent," New York Review of Books, September 26, 2013).

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A Genetic Link to Skin Cancer is Found by Data Mining of Patient Records November 24, 2013

In a paper published in Nature Biotechnology on November 24, 2013 thirty-six researchers lead by Joshua Denny, associate professor of biomedical informatics and medicine at Vanderbilt University, showed that data mining of electronic patient records is more cost-effective and faster than comparing the genomes of thousands of people with a disorder to the genomes of who people who don't have the disorder.

"To identify previously unknown relationships between disease and DNA variants, Denny and colleagues grouped around 15,000 billing codes from medical records into 1,600 disease categories. Then, the researchers looked for associations between disease categories and DNA data available in each record.

"Their biggest new findings all involved skin diseases (just a coincidence, says Josh Denny, the lead author): non melanoma skin cancer and two forms of skin growths called keratosis, one of which is pre-cancerous. The team was able to validate the connection between these conditions and their associated gene variants in other patient data.

"Unlike the standard method of exploring the genetic basis of disease, electronic medical records (EMRs) allows researchers to look for genetic associations of many different diseases at once, which could lead to a better understanding of how some single genes may affect multiple characteristics or conditions. The approach may also be less biased than disease-specific studies.

"The study examined 13,000 EMRs, but in the future, similar studies could look benefit from much larger data sets. While not all patient records contain the genetic data needed to drive this kind of research, that is expected to change now that DNA analysis has become faster and more affordable in recent years and more and more companies and hospitals offer genetic analysis as part of medical care. When researchers have millions of EMRs at their finger tips, more subtle and complex effects of genes on disease and health could come to light. For example, it could allow for important studies on the genetics of drug side effects, which can be rare, affecting maybe 1 in 10,000 patients, Denny says" (http://www.technologyreview.com/view/521986/genetic-link-to-skin-cancer-found-in-medical-records/, accessed 11-25-2013).

Denny et al, "Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data," Nature biotechnology (2013)doi:10.1038/nbt.2749 

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