DNA…From Blueprint to Brick

In 2005, Caltech researcher Paul W. K. Rothemund made a smiley face. In fact, he made about 50 billion of them. Other than the sheer amount, what was remarkable about the accomplishment was what he made his smiley faces from — DNA.

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Some of the 50 billion smiley faces made out of DNA; each is about 100 nanometers in size.

Rothemund’s tour de force lab accomplishment was one of the most highly visible milestones in the emergence of a new scientific community. Rather than seeing DNA as primarily an information containing molecule – a blueprint – DNA nanotechnologists treat the iconic molecule as something to build with – a brick.

For much of the late 20th century, scientists, writers, and the general public imagined DNA as information. It was code in the form of a chemical, a molecule that directed our development and determined our destiny. This discourse served to organize, guide, and inform the research agenda of scientists for decades.

Starting in the late 1970s, an interdisciplinary group of chemists, crystallographers, molecular biologists and computer scientists began to reconceptualize what DNA was and what people might be able to do with it. The main person – for years, really the only person – at the vanguard of this effort was Nadrian “Ned” Seeman. In the late 1970s, Seeman, a biochemist whose main field of expertise was crystallography, was an assistant professor languishing in the biology department at SUNY-Albany.

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Seeman, 1978. (image courtesy of Seeman)

Seeman worked with complex organic molecules. These are notoriously difficult to crystallize. As a result, Seeman, about to come up for tenure, faced a dilemma captured nicely in the image below. Basically, “no crystals, no crystallography, no crystallographer.”

Screen shot 2014-09-24 at 17.33.36At the same time, Seeman was thinking about what it might be possible to build with DNA. Why DNA? First of all, it’s well studied – what historians of science call a model system. DNA’s structure is predictable, made of four different types of nucleotide subunits—adenine, cytosine, guanine, and thymine. The exact sequence of an organism’s DNA is determined by what scientists call complementary base pairing: adenine always pairs with thymine; guanine connects with cytosine.

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This predictability allows scientists to synthesize strands of artificial DNA—a technique perfected and automated in the 1980s—which, when properly treated in the lab, can link up to form a desired structure.

Seeman was thinking about a particular form of DNA that occurs during a process known as genetic recombination. This involves the breaking and rejoining of two homologous DNA double helices as shown below. If the two DNA molecules have regions of similar nucleotide sequences, they can “cross over” and form a novel nucleotide sequence. A crucial intermediate stage in this recombination of DNA is a structure known as a Holliday junction (named after the British molecular biologist who first proposed it in 1964).

Screen shot 2014-09-24 at 17.13.59In 1979, Seeman started doing computer modeling of these Holliday junctions. His goal was to try to better understand their motion during recombination. Seeman soon recognized that in principle one could – using synthetic DNA – create junctions that didn’t move.

To do this, Seeman would have to take advantage of another feature of DNA. This is called a “sticky end.” These occur when one strand of the double helix extends several base pairs beyond the other strand. This presence of sticky ends meant, Seeman reasoned, that one could – using junctions as well as sticky ended cohesion – build DNA structures that formed lattices and networks.

In Seeman’s telling, his epiphany came while sitting in a bar in Albany. Crystallographers, not surprisingly, are quite familiar, even fond, of works by M.C. Escher given the Dutch artist’s focus on periodicity, symmetry, and the overall representation of objects in space. Seeman recalled Escher’s 1955 painting Depth:

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M.C. Escher, Depth, 1955 woodcut and its DNA analog in form of 6-armed junction.

Seeman realized that the fish in the Escher picture were just like a 6-arm junction arrayed in periodic fashion. Wondering if he might be able to make a similar structure from branched DNA molecules, Seeman proposed his ideas in an article that came out in the Journal of Theoretical Biology in early 1982.

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Header and key passage in Seeman’s 1982 article, with subsequent citation count.

It’s important to note where Seeman’s paper – now cited nearly 900 times – appeared. It was in a journal of theoretical biology. Seeman was noting that it was possible to make these DNA lattices…but he had yet to demonstrate this could actually be done in the lab.

Doing this required overcoming one key obstacle – getting the right amount and right sequence of DNA. In the early 1980s, one could buy synthetic DNA but it was very expensive. A strand of DNA with the desired order of base pairs, maybe only 10-12 nucleotides, might cost around $6000.

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Synthetic DNA, which today can be made for pennies a base pair, was an expensive raw material c. 1980. (image courtesy of George Church).

So, Seeman opted for the cheaper but more time consuming option. Over the next several years, he learned the arcane craft of making DNA with custom sequences of nucleotide bases. A DNA synthesizer paid for by the National Institutes of Health became his lab’s most important piece of equipment.

In late 1983, Seeman finally published a paper in Nature that gave experimental proof of the theoretical idea he had published 18 months earlier. Working with Neville Kallenbach, then at University of Pennsylvania, they demonstrated that it was possible to construct an immobile DNA junction. Kallenbach left Penn for New York University and in 1988, recruited Seeman to NYU’s Chemistry department.

Two years later, working with his graduate student Junghuei Chen, he synthesized a DNA molecule that had ten strands. When combined with similar molecules, the result was a macromolecule with the “connectivity of a cube” – it was the first lab demonstration that one could make 3-D structures with DNA.

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Seeman and Junghuei Chen, 1990, with model of their DNA cube (image courtesy Seeman)

Seeman would later tell me that he always “regarded DNA as a four letter word” – referring to its four nucleotide bases and “not very interesting when it’s linear.” It was in the 3-D realm, building things with it that he found excitement.

Today, DNA nanotechnology is one part of the growing field of synthetic biology. Today, more than 60 labs – including Paul Rothemund’s at Caltech – are doing various forms of nanotechnology with DNA and RNA. To date, successes with DNA nanotechnology have included the construction of increasingly complex three-dimensional shapes, carrying out massively parallel computations, and building “DNA walkers” that can traverse a substrate and deliver “cargoes” of nanoscale particles.

For a historian of science, what is fascinating about this evolving field is this new interpretation of DNA. DNA made the transition from genes to machines. In the end, it all comes back to a fundamental shift in how researchers saw DNA: from a code to a construction material.

A 17th Century Space Race

In 1638, an entry appeared in the Stationers’ Register, the book maintained by London’s publishing industry that recorded names of new books for nascent copyright purposes. It noted the publication of a work called The Man in the Moone. Subtitled “A Discourse of a Voyage Hither,” it is regarded today as the first English-language work of science fiction.1 Its author was not, despite the cover’s claim, Domingo Gonsales – who is nevertheless an important part of the book – but rather an English cleric who had died five years prior.

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Francis Godwin (1562-1633). Source: National Portrait Gallery

Francis Godwin was born 1562 in Hannington, a small village about 100 kilometers west of London. Educated at Christ Church in Oxford, where he learned some mathematical astronomy, the moderate Calvinist later became bishop of Hereford where he served until his death.2 Sometime in the late 1620s, Godwin began to compose The Man in the Moone. The book’s incorporation of the era’s natural philosophy have helped scholars precisely date it. Godwin included, for example, discoveries from the “new astronomy” as catalyzed by Copernicus, Galileo, and Kepler.

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Cover of Godwin’s book

The protagonist of Moone is Domingo Gonsales, a diminutive Spanish merchant and nobleman. Godwin’s choice was slightly daring as his book’s narrator came from a nation with which the kingdom of England was at war. As the story unfolds, Gonsales is forced to flee Spain after killing a man in a duel. After visiting the West Indies, Gonsales is stranded on a remote but “blessed Isle of St. Hellens.”

It’s on that speck of land that Gonsales finds a means of escape in the form of a “certain kinde of wild Swan.” Christened by Gonsales as gansas (Spanish for geese), the slight Spaniard trained 25 of them to draw him through the air. Gonsales contrives an “Engine,” a pulley-and-string frame to which he harnesses the geese. After trial flights around his island, he boasts of his plan to travel back to Spain so that he might “fill the world with the fame of my glory and renowne.”  Once aloft, however, Gonsales discovers the geese have their own intentions. The time of year is important here. As Godwin tells us, it was “now the season that these birds were wont to their flight away, as our cuckoes and swallowes doe in Spain toward the autumne.”

In the seventeenth century, many unresolved questions persisted around the causes for the annual migration of birds as well as their destination. One theory was that, come autumn, some birds migrated to the moon. Charles Morton, an English natural philosopher who himself emigrated to the American colonies, based his theory on his readings of both science and scripture. His Compendium Physicae claimed, with its own internal logic, that since no one knew where birds went in the winter months, one could just as well suppose that they flew off the earth.3

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Moon bound?

Back to Gonsales’s predicament: To his amazement and fear, “with one consent” the gansas rose up, “towring upward, and still upward.” The geese, yielding to their autumnal urge to fly – where? – soon continued to pull the Spaniard away. But, soon, the birds seemed to labor less. The lines connecting Gonsales to his geese slackened and he found himself “having no manner of weight.” Freed finally from the earth’s pull, Gonsales found himself moon-bound.

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Detail showing Gonsales’ flight.

Not all ideas from early seventeenth century natural philosophy appealed to cleric Godwin. Although offering one of the first descriptions of weightlessness, Godwin’s book attributed this curious state to diminishing magnetic attraction, not gravity. As Gonsales relates, he would not “go so farre as Copernicus, that maketh the Sunne the Center of the Earth, and unmovable.” Nonetheless, Bishop Godwin adopted an idea from Galileo – that the motion of the Jovian moons might be used to keep track of time’s passage – and had Gonsales use the Earth’s diurnal rotation to record the duration of his voyage. Slight in size and speculative in form, The Man in the Moone nonetheless gives a gauge for the degree to which new astronomical knowledge reached a wider audience in the 17th century.

In Godwin’s telling, Gonsales and his gansas touched down on the lunar regolith in mid-September 1599 after a twelve day voyage. In actuality, this fictional moon landing occurred in the midst of a seventeenth century space race.

The same year that Godwin’s book appeared – 1638 – another lunar-themed work came out. John Wilkin’s The Discovery of a World in the Moone showed similarities between our planet and its moon. In it, he referenced the tales related in Godwin’s book. Wilkins later went on to co-found the Royal Society, a group occasionally mocked for its far-fetched ideas.

We might imagine 1638 – the year both Godwin and Wilkins’ books appeared – as “England’s lunar moment.”4 But unlike the Cold War version, it was imagination, not hardware, that allowed early English readers to bound around the lunar landscape.

Godwin’s speculations were aided by advances in scientific instrumentation and publications which helped bring the moon closer. In 1609, for instance, telescopic observations revealed the moon not as the unchanging sphere as imagined by Aristotle but earth-like with a cratered and mountainous landscape. Moon gazing grew in popularity. Hundreds of thousands of almanacs, printed annually in Stuart England, told viewers when they could see lunar eclipses. Two of these events, in fact occurred in the same year that Godwin and Wilkin’s books appeared, fueling the fad.

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Example of 17th century almanac

What of the lunar dwellers who greeted Domingo Gonsales and his gansas? Inhabiting an environment lush with trees and shrubs “at least three times so high as ours,” they were likewise giant-size but with a “color and countenance most pleasing.” Godwin made his “Lunars” – to the relief of some theologians – Christian. Kind, devout, and morally superior to earthlings, Godwin contrasted his more perfect lunar state, more than a century after Thomas More penned Utopia, with the imperfect world marred by religious conflict, political turbulence, and outright warfare that he (and Gonsales) called home.

Despite some derision, Godwin’s book enjoyed a long life, both in England and on the continent. Within two decades after its publication, translations of Moone in Dutch, German, and French circulated. The playwright and libertine Cyrano de Bergerac encountered Bishop Godwin’s book soon after copies of it appeared in Paris in 1648.

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Under the impression that the sun “draws up” dewdrops, Cyrano de Bergerac suggested fancifully that one might fly by trapping dew in bottles and standing in sunlight.

In de Bergerac’s own L’Autre Monde, ou Les Etats et Empires de la Lune, a fictional traveler goes to the moon and there meets “a little man…an European, native of Old Castile” who had found “a means by Birds to arrive at the Moon.” No longer a welcome guest, in Cyrano’s re-telling, the man – clearly, modeled after Domingo Gonsales –  has been demoted by the moon dwellers to the status of a pet.

Although woven into English comic opera and drama, Godwin’s book was gradually occulted until the mid-nineteenth century. Rediscovery followed, first by Edgar Allan Poe – the protagonist in his 1835 story “The Unparalleled Adventure of One Hans Pfaall” was also a lunar voyager of diminutive size – and then H.G. Wells who adopted some of Godwin’s ideas for his 1901 book The First Men in the MoonBut all of these owe a debt to the flock of lunar-themed books that circulated around Europe during the seventeenth century’s space race.

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  1. Kepler’s 1634 Somnium is generally seen as the pioneering sci-fi work. []
  2. Information on Godwin as well as his book comes from Francis Godwin, The Man in the Moone, ed. William Poole (Ontario: Broadview Press, 2009 [1638]). Italics are in the original. All quotes from Moone come from Poole’s excellent edited version. []
  3. Thomas P. Harrison, “Birds in the Moon,” Isis, 1954, 45, 4: 323-30. []
  4. David Cressy, “Early Modern Space Travel and the English Man on the Moon,” The American Historical Review, 2006, 111, 4: 961-82. []