S3.09 Twisted history: the true story of the double helix
Kat: Hello, and welcome to Genetics Unzipped - the Genetics Society podcast, with me, Dr Kat Arney. The names of James Watson and Francis Crick are inextricably linked with the discovery of the DNA double helix. And if you’ve been paying attention, you’ll also know that credit is due to Rosalind Franklin, Maurice Wilkins and Ray Gosling too.
But what about Elwyn Beighton, Fred Griffith or Rudolf Signer? In this episode we’re unwinding history to uncover some of the less well-known stories behind the discovery of the structure and function of DNA.
“History is written by the victors.” It’s a quote often attributed to Winston Churchill, and it’s certainly true of many discoveries in science, where being the first to publish a major finding is enough to secure your name in the history books (or at least in the science textbooks…)
Like many science enthusiasts, I read the book The Double Helix when I was a student. It’s a dramatic tale of how American geneticist James Watson and British molecular biologist Francis Crick discovered the structure of DNA back in the early 1950s. Of course, being written by Watson himself, it’s no surprise that he’s the dashing hero of the story.
Big names like Watson and Crick take much of the glory for the discovery of the structure of DNA, while others like Maurice Wilkins, Rosalind Franklin and Ray Gosling are increasingly recognised for their contributions - as we discussed back in episode 16 of our first series from June last year.
But there are so many more overlooked names and wonderful stories that deserve to be told, even around something as seemingly well-documented as DNA. Someone who’s spent plenty of time unearthing them is Gareth Williams, author of 'Unravelling the Double Helix: The Lost Heroes of DNA.'
Gareth: “In fact, the story is much more complex than you would believe from simply reading The Double Helix.”
Ya think??
Discovering DNA
Let's start by setting the record straight: James Watson and Francis Crick did not 'discover DNA', as is sometimes mistakenly said. They did decipher its double-stranded structure, earning themselves a share in the 1962 Nobel prize in physiology or medicine together with Maurice Wilkins. But they did not discover its existence. That honour goes to someone who came long before.
Gareth: "In fact, the story does not begin in the 1950s. It actually begins in 1868 with a guy who set out to be a doctor, but because he was deaf, having caught typhus in childhood, he couldn't hear anything through the stethoscope, so he had to abandon medicine as a career, and he went into the emerging field of biochemistry."
This man was Johannes Friedrich Miescher, who we talked about back in episode 5 of this current series, Poop, Pus and the Manhattan project. Miescher was the first person to isolate nuclein - as DNA was then known - from the white blood cells in pus-soaked hospital bandages, carrying out detailed studies on its properties.
Despite his enthusiasm for nuclein, Miescher was convinced that it was too simple a molecule to transmit hereditary traits as it only contained four building blocks, or bases. Instead, he was confident that proteins with their 20 amino acids must play a significant role in passing on genetic information.
Unfortunately, Miescher became distracted by other research and responsibilities - and was possibly disillusioned by the obstructions he encountered while trying to publish his findings - so he didn’t publish any work on nuclein after 1877.
In 1894 he contracted tuberculosis and eventually moved to a clinic in the Alps. There he attempted to complete unfinished manuscripts of his work, but he was too weak and he died in 1895, aged just 51. In a prophetic letter to Miescher just before his death, his former mentor Carl Ludwig wrote:
“As hard as it may be, you have the comfort of having achieved everlasting accomplishments; you have made the centre, the core of all organic life accessible to chemical analysis; and however often in the course of centuries to come, the cell will be studied and examined, the grateful descendant will remember you as the ground-breaking researcher."
After Miescher’s death, his uncle Wilhelm His collated his unfinished work and wrote in the introduction:
“The appreciation of Miescher and his work will not diminish; on the contrary, it will grow and his discoveries and thoughts will be seeds for a fruitful future.”
Of course, he was right.
Wanted: Dead or alive
The next development in the story of DNA came as many significant scientific discoveries do, by looking for something else. And our next character in the story is Frederick Griffith - a medical officer in the British Army in the First World War.
Gareth Williams: “He was an expert on the pneumococcus, which is a particularly, or it can be a particularly unpleasant germ that causes lobar pneumonia in people. In the days before antibiotics, this carried off lots of fit young folk. And it was the disease lobar pneumonia was known as the captain of the man of death because it had such a high mortality.”
Fed up with watching service men succumb to pneumonia, Griffith began to study Streptococcus pneumoniae, the bacteria responsible, in the hope of developing a vaccine against the disease. Unfortunately, he didn't find the vaccine, but he did discover what he called the 'transformation principle.'
Gareth: “And what Fred Griffith did and was not really recognized for until long after his death was to exchange genetic material between different kinds of pneumococci, and he was able to change them into well from essentially harmless strain into a completely lethal strain.
So the harmless ones, you could take a thousand million of them and inject them into a mouse and the mouse would be absolutely fine. Yet you could take just one single bacterium and bang that into a mouse and 12 hours later the mouse would be dead, and its blood would be full of living pneumococci.
So what Fred Griffith did was to take the harmless ones and mix them with an extract of dead lethal ones and show that somehow something in that dead extract was able to insinuate itself into the living harmless ones and turn them into killers.”
Although Griffith identified that there must be an agent carrying genetic information that survived the heat treating process that killed the bacteria, the question of precisely which substance carried the information remained, with many scientists firmly believing that it was proteins that fulfilled this role and that nuclein simply acted as a support material within chromosomes.
In 1945, Oswald Avery, Colin MacLeod, and Maclyn McCarty demonstrated that Griffith's “transforming agent” was not a protein, but DNA, suggesting that DNA may function as the genetic material.
Their experiments were similar to Griffith’s, but they removed proteins and polysaccharides from the heat-treated virulent strains of pneumococci, leaving only the DNA. The DNA of the virulent pneumococci successfully transformed the harmless bacteria.
Gareth: “This should have been the moment when people finally agreed that actually genes were made of DNA, albeit in bacteria, but probably in other species as well.
But the thing is that at the time people believed that proteins were the only biochemical substances that were versatile and clever enough to have the instructions or the billions of instructions of life engraved in them because of the diversity of their structures. DNA was thought of as a rather small, boring molecule that couldn't possibly be clever enough to carry the genes.
Avery then had to fight an uphill battle against even a DNA expert in his own institution at the Rockefeller in New York who used every opportunity to shoot down Avery's notion that DNA was the stuff of genes in bacteria.
Avery, I think is one of the characters I feel the most empathy with, together with Fred Griffith - this was a very hardworking, fastidious man, slightly odd I have to say, but he was nominated for a Nobel prize over 40 times and he never made the cut.
The reason for that is that he was up against people who if you like were ‘protein supremacists’ - they believed that only proteins were clever enough to be stuff of genes and therefore they just torpedoed the notion that DNA could actually be it.”
Proteins were the hot topic in the 1940s, with protein supremacists dominating the Nobel prizes, including in 1946, when researchers Wendell Stanley won a Nobel for apparently ‘proving’ that the active component of the tobacco mosaic virus was a protein, confirming to many that proteins carried genetic information.
In 1952, Alfred Hershey and Martha Chase published the most convincing argument for DNA as the genetic material so far, based on their work with bacteriophage viruses, which - as the name suggests - love to infect bacteria.
Thanks to a little help from a humble kitchen blender, Hershey and Chase showed that during infection, viral DNA enters the bacteria, while viral proteins do not. For more about their infamous blender experiment and the life of Martha Chase, take a listen to the “Kitchen Aid" story from episode 10, Not Just the Wife, that came out in March last year.
After proving that DNA contained genetic information, the next step was to figure out how it stored the information and how it replicated itself so easily. And for that, scientists needed to know a lot more information about the structure of DNA.
Although its general chemical composition was known, and the fact that it formed long strands inside cells - something we discussed in episode 12, Strands of Life - nobody knew what DNA looked like right down on the molecular level.
Several researchers had already proposed structures for DNA, including Phoebus Levene, who carried out detailed research on the composition of the four ‘building blocks’ of DNA, also known as bases or nucleotides - that’s adenine, cytosine, thymine and guanine.
Levene came up with a ‘tetranucleotide hypothesis’, suggesting that DNA was made up of small squares of the four different nucleotides, like little four-link chains, which all stacked on top of each other. But while it was visually appealing, his idea was too ‘boring’. If every stacking square was exactly the same, how could they possible encode all the information required for life?
As people began to believe DNA was more complex and could transfer hereditary traits, more proposed structures followed.
Gareth: “There'd been a three standard three-stranded structure with three, three helices would together, a bit like sort of tangle of amorous snakes. And this was actually proposed by Linus Pauling, you know, one of the great fathers’ grandfathers of 20th-century chemistry.
And this structure was not just bad. It was awful because somebody looked at and said that thing would just blow itself up. There's just no way that it could be held together in a stable structure.”
In 1949, a young Norwegian scientist called Sven Furberg, came tantalizingly close to unravelling the structure of DNA. But his supervisors’ political preoccupations meant that he paid little attention to Furberg and his models, and so Sven eventually abandoned the idea.
Around the same time, at King’s College London crystallographer Maurice Wilkins and his team - which would soon include a talented young female scientist called Rosalind Franklin - were twisting their thoughts around various helical structures.
Gareth: “And Maurice Wilkins at the time was thinking about possibly two helices possibly three, possibly even four.”
Of course, it was Watson and Crick that eventually deciphered the correct double helix structure, but they couldn’t have done it without some vital work from other scientists. And no, I’m not just talking about Franklin.
The Crystal Maze
The next thread in the story of DNA brings us to Herisau, Switzerland in the early 1900s. Born into a family that had been textile manufacturers for six or seven generations, Rudolf Signer was surrounded by chemistry from a young age.
As a youngster he was fascinated by astronomy and philosophy, but his father put him off pursuing either of these interests any further, arguing that Rudolf wouldn’t be able to earn a living from philosophy and it would be much more practically useful to study maths, physics or chemistry. And given the family business of dyeing and bleaching fabrics, chemistry it was.
As a student at the Swiss Federal Institute of Technology in the 1920s, Signer was particularly fascinated by nature. He went on excursions with the Institute’s botanists and took a beautiful collection of plant photographs.
It’s not surprising, then, that he chose to work on the molecules of life, studying with Hermann Staudinger during both his undergraduate work and PhD.
Sometime later, Signer, now an expert in macromolecules, invented a technique for measuring the molecular weight of polymers. It was called flow birefringence. In 1938, he collaborated with cell biologist Torbjörn Caspersson to apply his method to measure the molecular weight of DNA.
Their work showed that the DNA molecules were long, thin fibres - unusually large for molecules - with the bases sticking out perpendicular to the long axis of the strand.
Signer’s time with Caspersson highlighted to him how vital studying DNA could be. But he also recognized that isolating pure DNA was essential for this kind of research. Unfortunately, when cells are broken apart, DNA rapidly breaks apart too.
Signer and his students set about working on improving the extraction process so they could obtain pure DNA with very long chains. They were successful, and Signer became famous for his DNA extraction method.
Signer’s techniques yielded DNA molecules with a molecular weight of 7 million, which was extraordinarily high for the time. Eager to share his techniques, Signer gave a lecture at a symposium in London in 1946, where PhD student Raymond Gosling was in attendance with Maurice Wilkins.
Gosling recalled:
"Signer gave a lecture at the Royal Society on this method that he'd developed to separate out the DNA from the nuclear protein and so produce high molecular weight pure DNA. Signer asked at the end of the lecture if anybody would like some of this material, and he had a specimen tube full of this freeze-dried material. Only two people put their hand up. I'm glad to say that Maurice was awake enough to put his hand up!"
Gosling worked together with Rosalind Franklin at King's, conducting X-ray crystallography on Signer’s DNA. Using the sample, they obtained their famous Photo 51, which shows a big, bold X, revealing that DNA had a regular, repeating helical structure.
The photo was the clearest image of DNA that had been obtained so far, and Wilkins once attributed the clarity of the image to the DNA obtained from Signer.
Of course, Photo 51 eventually made its way into the hands Watson and Crick, who used it to decipher the full double helix structure of DNA. To find out more about that story, make sure you listen the story 'double helix trouble' in episode 16 from June last year.
Here’s author Gareth Williams again.
Gareth: “But the interesting thing about the big bold capital X that we would instantly identify as Photograph 51 is that a very similar picture was taken a year before Photograph 51 and actually before Maurice Wilkins took similar photographs, which he did with living sperm from squid.
This photograph is not terribly well known. It’s called B299 and it was taken by a PhD student in Leeds. His boss, a man called Bill Astbury, who'd made a reputation on x-ray diffraction pictures of various fibres, had been sent a sample of DNA. And he'd instructed the PhD student Elwyn Beighton to take a picture of it. He took it, and because the picture that came out was so bizarre, it was nothing like a normal fibre of any sort, he decided that it wasn't worth pursuing.
Elwyn Beighton was put back on his original project, and that photograph, which looks exactly like photograph 51 was never published, and it was never even presented at the meeting. So it's as though it never happened.”
I bet Beighton was kicking himself when the 1962 Nobel Prizes were announced.
So there you have it, a few more chapters of the real story of the double helix with all its twists and turns. As James Watson himself once said:
"Science seldom proceeds in the straightforward logical manner imagined by outsiders. Instead, its steps forward (and sometimes backward) are often very human events in which personalities and cultural traditions play major roles.”
And although I do find these personalities fascinating - and sometimes pretty repellent, as in the case of Watson - the true star of the story as far as I’m concerned is the molecule itself.
Gareth: “Well, it is beautiful, as you say. It’s got the beauty of simplicity but it’s also got the beauty of purpose. It's not just a beautiful structure, it's a structure with function and the function that makes each of us, who we are.”
That’s all for now. You can find Gareth William’s book, Unravelling The Double Helix: The Lost Heroes of DNA from all good bookshops, and evil ones too...
Next time, we’ll be taking a virtual trip to Africa to discover more about the roots of genetic diversity and what we can learn about history and culture from the storybook written in the human genome.
For more information about this podcast including show notes, transcripts, links, references, music credits and everything else head over to geneticsunzipped.com You can find us on Twitter @geneticsunzip and please do take a moment to rate and review us on Apple podcasts - it really makes a difference and helps more people discover the show.
You can find us on Twitter @geneticsunzip and please do take a moment to rate and review us on Apple podcasts - it really makes a difference and helps more people discover the show.
Genetics Unzipped is presented by Kat Arney, with additional research and scripting by Emily Nordvang. It is produced by First Create the Media for The Genetics Society - one of the oldest learned societies in the world dedicated to supporting and promoting the research, teaching and application of genetics. You can find out more and apply to join at genetics.org.uk
Our theme music was composed by Dan Pollard, and the logo was designed by James Mayall, and production was by Hannah Varrall. Thanks for listening, and until next time, goodbye.
References and credits
Music and sound effects all licensed from Epidemic Sound or Envato
Gareth Williams - 'Unravelling the Double Helix: The Lost Heroes of DNA.'
Rags before the riches: Friedrich Miescher and the discovery of DNA
A Speculative History of DNA: What If Oswald Avery Had Died in 1934? - Matthew Cobb
The tetranucleotide hypothesis: a centennial István Hargittai
The Rosalind Franklin papers: The DNA Riddle: King's College, London, 1951-1953
Raymond Gosling: the man who crystallized genes - Naomi Attar
