John Randall’s MRC Research Unit and Rosalind Franklin‘s role at Kings College
http://pharmaceuticalintelligence.com/2013/04/05/john-randalls-…ranklinds-role/
Larry H Bernstein, MD, FACP
My Personal View on the DNA Discovery
If it had not been for John Randall’s creation of an MRC Research Unit dedicated to the study of the physical and biological mechanisms of single cell division,
- the structure of DNA would not have been revealed in the U.K.
- Most likely it would have been discovered in Linus Pauling’s laboratories in America.
- Watson and Crick building atomic models in Cambridge and
- Wilkins and Franklin et al., exploring x-ray diffraction patterns at Kings College in London.
- funded in perpetuity with the avowed intent of applying “The Logi of Physics to the Graphi of Biology”—
- in particular to the mechanisms causing division of living cells.
In the 1940s it was still being debated as whether it was the nuclear protein, the DNA or both together that were instigating cell division.
Randall was convinced by the work of Avery and others that DNA alone was the agent of division.
Accordingly he had several avenues of research progressing in his laboratory concerned solely with DNA.
Reporter: Larry H Bernstein, MD, FACP
Enter Raymond Gosling, participant and remembrance
The Genesis of a Discovery: First Steps
Raymond Gosling, D.Sc.
expose them to x-rays, edge on, in the hope that the resulting diffraction pattern would reveal something of their DNA structure. The result
was a disappointing, fuzzy fiber diagram.
Meanwhile Maurice Wilkins had attended a lecture at the Royal Society by Rudolf Signer, a Swiss biochemist who had managed to extract DNA
from calf thymus gland at a very high molecular weight—around 12 million. At the end of his lecture, Signer offered some freeze-dried samples
of this sodium salt of the DNA, which Wilkins quickly accepted. Back in the lab he found that fibers drawn from a water gel of this material were
highly birefringent.
I asked him if I could try to get a diffraction pattern from a specimen of these fibers to compare
- as a gold standard with those from my various attempts to persuade rams’ sperm to lie flat.
machine produced a result not much better than my sperm flakes. Most of the atoms in the fibers were the same as the air within the camera. We ad to
- displace the air with hydrogen.
taken in 1950 [Prof. Ray Gosling]
- so form micro crystallites throughout each fiber. (The result is shown in the Figure).
that if DNA was the genetic material then I had just shown that
- genes could crystallize. (Wilkins reacted enthusiastically)
- the concept of the sphere of reflection and reciprocal space.
- The measurement of layer—the line separation in the pattern shown in the Figure gave the C axis repeat of the unit cell.
- Trial and error assignment of HKL index values (reciprocal lattice points) to the other reflections, suggested that the unit cell was
- Monoclinic C2 with values of A=22.0 Å, B=39.8 Å, Beta=96.5°, C=28.1 Å.
Secret of Life
a novel high intensity x-ray tube, kindly lent to us by Ehrenberg and Spear at Birkbeck, and a microcamera allowing us to obtain diffraction patterns
from single fibers of NaDNA. This was something that no other lab was currently able to do.
Randall’s response to this was to headhunt for an experimental scientist versed in using x-rays to solve the molecular structure of para-crystalline
material, such as was our sodium salt of DNA.
He found Rosalind Franklin, working in Paris in 1950, needing her to join us at Kings and lead the effort in
- solving the puzzle of our beautiful diffraction pattern.
Later that year there was a meeting of Franklin, Stokes, and myself in which I was formally handed over to Franklin as her assistant, i.e., transferred
from the Wilkins/Stokes team to work exclusively with her.
Seeds of Conflict
by a letter from Randall, that she would be in charge of the work of solving the structure. I realized later that she was unaware of the special position of Wilkins
vis-à-vis Randall in the structure and politics of the laboratories as a whole.
The seeds of conflict were sown. In retrospect I should have realized this and tried to prevent this conflict.
Consequently, he went to Bragg’s unit at Cambridge, where he met Francis Crick who knew our work, as he was a close friend of Wilkins.
we bubbled through to displace the air in our camera. So we were then able to take the same specimen through stages of water content from dry (disorientated pattern) to
92% humidity and to do this with a single fiber.
The Elegance of Franklin’s Science
We realized the published fiber diagrams up to now had been mixtures of these two forms. That I had produced a pure form of A with Maurice’s multifiber specimens was serendipitous.
and getting a spark from 50,000 volts on the rather old x-ray tube.
As to the structure, it was obvious from the B pattern— Photo 51—that at high humidity the molecule was helical. From Stoke’s theoretical math we found that the
- diameter was 20Å and the repeat distance was 34 Å containing 10 nucleotides per turn of the helix with a slope of 40°.
Direct Structural Information
- calculate a Patterson Function from the data.
- This would show helical or asymmetric chains (without the need to build models).
and the sugar rings coming out to the bases on the outside. We knew the Na/P complex must be on the outside of the structure because the water went in and out so easily.
It was the only time Crick had seen Watson at a loss for words! With hindsight it is easy to see that the structure they had built must be wrong. It is known that
- there are 3 billion base pairs in the human genome.
- At 34Å thick, this would mean a length of 102 cm,
- it required greater flexibility to allow folding of the structure to fit into the cell nucleus.
Off and On Again Model Building
We returned to Kings and started with renewed vigor on our
- intensity measurements
- correction factors
- Patterson function calculations
However some months later, on learning that Pauling was actively thinking of DNA structure, Bragg lifted his ban on model building!
Watson and Crick began building models again, this time using our data as to helical radius 10Å, and to the number of nucleotides along the fiber axis
per repeat interval, 10 in 34Å, and the space group of structure A, Monoclinic C2. This permitted Crick to rightly postulate
- two chains per lattice point related by a diad axis, i.e., one going up and one going down.
It was so elegant, it must be right. Frankin and I examined our Patterson data and everywhere we looked we could see indications of a double helix.
The Aftermath and a Kind Appraisal
heard her opinion of the current controversy on the cloning of stem cells. The laws of the physical universe will always apply, and it is only our interpretation
and use of the data that may be wrong. However, when experimenting with living material, even the protocol of the experiment may be questioned.
I believe Franklin would have advocated a global approach to the regulation of such work. We are now facing
- direct manipulation of the evolution of our species
- and the creation of new transgenic life forms.
A problem probably more important than global warming.
Raymond Gosling, D.Sc., carried out research on the structure of DNA with Maurice Wilkins and Rosalind Franklin at King’s College in London,
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Related articles
- King’s College was a hotbed for DNA discoveries (morningstaronline.co.uk)
- Photo 51 and Double Helix Structure of DNA (dshenai.wordpress.com)
- Written out of history (morningstaronline.co.uk)
- The Day Scientists Discovered the ‘Secret of Life’ (pbs.org)
- DNA’s double helix: 60 years since life’s deep molecular secret was discovered (guardian.co.uk)
- ‘Taking a photo’ of DNA helices with an Environmental Scanning Electronic Microscope (nanowerk.com)
- DNA structure and Oligonucleotides (pharmaceuticalintelligence.com)
- Rosalind Franklin and the 60th Anniversary of the DNA double helix (rabbitscience.wordpress.com)
- Watson and Crick Discovered DNA 60 Years Ago Today (gizmodo.co.uk)
Rosalind Franklin used X-ray crystallography to help visualize the structure of DNA. (Photo credit: Wikipedia)
DNA Biochemical structure (Photo credit: Wikipedia)
A fragment of DNA, the chemical sequence that contains genetic instructions for the development and functioning of living organisms (Photo credit: Wikipedia)
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.