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Do curso por University of Geneva

Classical papers in molecular genetics

89 classificações

University of Geneva

Classical papers in molecular genetics

89 classificações

You have all heard about the DNA double helix and genes. Many of you know that mutations occur randomly, that the DNA sequence is read by successive groups of three bases (the codons), that many genes encode enzymes, and that gene expression can be regulated. These concepts were proposed on the basis of astute genetic experiments, as well as often on biochemical results. The original articles were these concepts appeared are however not frequently part of the normal curriculum of biologists, biochemists and medical students. This course proposes to read study and discuss a small selection of these classical papers, and to put these landmarks in their historical context. Most of the authors displayed interesting personal histories and many of their contributions go beyond not only the papers we will read but probably all their scientific papers. Our understanding of the scientific process, of the philosophy underlying the process of scientific discovery, and on the integration of new concepts is not only important for the history of science but also for the mental development of creative science.

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Session 4

When DNA was found to be the genetic material, it was not known how this molecule could carry information. The structure of DNA thus became of critical importance. The available X-ray images obtained by M. Wilkins and R. Franklin only yielded a rough picture, and even R. Franklin, who had the clearest diffraction data, could not decide whether the molecules contained two or three strands. Both Pauling and Watson and Crick used molecular models with known inter-nuclear distances (bond length) and bond angles to predict a structure. While the model of Pauling was hardly realistic, since it used the protonated form of the phosphate, the model proposed by Watson and Crick proposed that DNA consists of a pair of DNA strands. Furthermore, it indicated that any nucleotide sequence could be accommodated in the structure. The only central biological issue that was addressed in the first paper was replication, and the famous sentence was really nothing more than a priority claim. Much more biology was discussed in the second paper. It was assumed that base pairing is sufficient to account for the fidelity of replication. The importance of DNA polymerase in replication fidelity was first demonstrated by Speyer.

Conheça os instrutores

Dominique Belin
Professor
Department of Pathology and Immunology University of Geneva Medical School

[MUSIC]

Okay, so you have to imagine these two guys.

Francis Crick is in his 30s.

He doesn't have PhD yet.

Watson, Jim Watson is 23.

He has a PhD as a postdoc.

He's into his first or second postdoc depending on how you want to count.

They decided to play with models and

they had, A lot of help.

They had help from two people.

The most important is Donohue, who they thank in their paper.

The other help they had was from Pauling’s son, who was a postdoc in the lab and

got them the pre-prints of his father's triple helix model.

And they immediately knew that the model was wrong, but

it helped them think about it.

So basically, they were doing, trying to put models

together, and they forgot that DNA is very hydrated.

And that DNA has sodium salt around it.

And so it had to be hydrated.

And then of course, this mistake was compounded by the fact that at one time,

both Crick and Watson were supposed to go to London to talk to Rosalind Franklin,

but Crick couldn't go, and so Jim went alone.

But Jim didn't know anything about crystallography, and so he confused

asymmetric units and unit cell, which are two different things in crystallography.

And so of course he didn't understand what the other one was talking about.

Donohue was critical because he told them

what is the arrangement of the atoms in the bases.

And the arrangement in the atom is not what was in the textbook at the time.

Donohue told them the exact arrangement of atoms in the bases.

So in the bases you have to simplify carbon,

oxygen, and carbon.

These can be linked in two different ways.

What is called a keto and of course there is a fourth bond here.

And what is called an enol.

Which is the C, alcohol, which is basically an alcohol, and

a double bond here.

You can count the electrons and they are the same.

It's a flat structure in both cases.

But in one case you have an oxygen with a cloud of electrons here.

In this case, you have a little cloud and

you have a proton which can be given to an electron.

So these structures have very different chemical reactivity,

chemical bonding properties, although they look the same and

they are, of course here, though they're hydrogen, the number of atoms is the same.

So Donohue told them that, in the textbook, that was the structure.

And Donohue told them this is real.

And that was extremely important.

And basically, once they realized that, Watson managed to find

the base pairing, namely the A with the T and the G with the C.

Watson was supposed to work on the crystallization

of myoglobin with Kendrew which he didn't do.

So they have something close to a structure, but

they are not sure whether it's a real structure.

They don't have the two pictures from London

and they only have a vague idea of what the pictures are.

And they decide nevertheless, that they're going to publish their model,

because they believe that what they know about the data from London

is compatible with their model and their other data compatible with their model.

And so, they decide to go ahead.

So you're going to have three papers appear in the same issue,

one after each other.

So this is a picture that shows Watson and Crick, with a tie on so

they look respectable, around a model of DNA,

which is close to the kind of model they were using.

This has nothing to do with the way they were working.

This is a complete reconstruction of what they wanted us to believe reality was.

They were not working like that.

But that doesn't matter.

Okay, so now we're going to go through the paper.

Before we go through the paper, remember, Watson and

Crick have a model which is a theoretical model.

Wilkins has images.

Rosalind Franklin has images.

Now, Rosalind Franklin is a very tough scientist.

She's a very good scientist, but she's tough.

And she's tough because she comes from a family where her parents didn't wanted her

to do science.

She comes from a relatively rich Jewish family and

she was supposed to marry a banker or something, not have an independent career.

So she had to prove herself or she thought she had to prove herself.

In private, she was apparently an extremely nice person.

But in the field, or

in the lab, she was extremely competitive and quite aggressive.

And to the point that people don't realize that, for instance,

she managed to get some very pure DNA from a guy in Bern, named Signer, and

she refused to give that DNA to Wilkins, okay, in the same lab.

This is pretty bad behavior.

On the pretense that she'd work [INAUDIBLE] and so

she was entitled to keep the DNA.

Which was a little bit absurd because Signer sent it to the London lab.

I mean, he didn't care who.

So they were all three in a rush.

So they knew the London group would send the paper.

So they send their paper assuming that everything would fit, more or less.

But the model was not built on the images of London.

Nobody model builds on any other

than putting bits and pieces of cardboard together until they fit.

Model building.

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