Meet Dr. Joachim Frank, Nobel Laureate


CUSJ 2018 ________________________________________________________________________________ 

Our editors Vikas Chelur CC’21 and Maria Trifas CC’21 
interviewed Dr. Joachim Frank in December 2017. Dr. Frank is a 
professor in Columbia’s Biological Sciences department who 
recently won the Nobel Prize in Chemistry in 2017 with Jacques 
Dubochet and Richard Henderson for their research in cryo-
electron microscopy. Here is a snippet of the interview where 
Professor Frank explains his research at different levels. 
 

VC (Vikas Chelur): Could you give us a brief explanation 
of your research in cryo-electron microscopy, as it pertained 
to you winning the Nobel prize from first how you’d 
explain it to a toddler?  
 

JF (Joachim Frank): Molecules are very tiny, tiny things that 
we have all over our body. And they bounce against each 
other and sometimes they recognize each other and say hi. 
And we want to know exactly what they’re doing and how 
they do this and how they say hi and why they want to get 
together and how this all makes our body work. This 
particular method that we developed makes it possible to 
see these molecules with very, very super microscopes that 
are better than light microscopes. 
 

MT (Maria Trifas): What about for a middle schooler? 
 

JF: Everybody knows that life processes are constituted by 
interactions of molecules. We have thousands of molecules 
of different kinds in each cell. And in a normal cell they 
function properly. In a deceased cell, there are many 
difficulties in these interactions, problems. And that’s how 
disease processes are developed.  

From that it follows that we need to have as complete a 
knowledge of all our proteins in the cells as possible. The 
existing technique for determining the structure of 
molecules to the atomic level (which means the highest 
resolution level) was by x-ray crystallography.  

For decades now, x-ray crystallography has been used 
to determine structures of biomolecules. And there are in 
fact more than a hundred thousand structures in the public 
database. They make possible what we call molecular 
medicine, because medicine nowadays is molecular 
medicine. It is based on the extensive knowledge of 
molecular structures. So, this whole database has a huge, 
huge gap. That gap exists because not all molecules can be 
crystalized. That’s essentially where electron microscopy 
jumps in.  

Electron microscopy can visualize molecules in a 
particular method that the three of us (Nobel laureates) got 
our prize for. It is a method of obtaining the structure of 
molecules from molecules in solution. And we call it single 

not because there is only one, but single because they are 
not attached to each other. So, we can simply look at many, 
many molecules that are randomly oriented in solution and 
on that basis, on the basis of the projection, we see the 
surface structure.  

There are two important methodologies involved. One 
of them is the way how all the information from the 
different projections have to be related to one another in 
order to find the orientations and then develop the three-
dimensional visualization. That technique I developed long 
before the ‘cryo’ part came along. So, I developed this with 
a very poor contrasting method that existed at the time 
which is called negative staining – so molecules were badly 
treated but they were still in some way propped up by the 
negative stain. And the images received their contrast 
essentially received their contrast as stain exclusion. So, one 
didn’t see the molecules, but one saw the stain, and what 
the molecules excluded. With this kind of visualization, I 
developed the algorithms, the computational techniques, to 
get all the way to the 3D structures.  

When I was just about finished with that, this other 
technique came along which allowed us to embed 
molecules in vitreous ice. That’s the contribution by Jacques 
Dubochet. The existing attempts to keep molecules in water 
by quickly freezing the sample in liquid nitrogen – that 
method doesn’t work, because on the interface between the 
grid and the liquid nitrogen, gas bubbles form, very 
quickly. These gas bubbles don’t transmit heat very 
efficiently, and that allows the ice to form crystals. 
Crystalline ice is dangerous for molecules; it sort of destroys 
them because it expands. And besides, it also has its own 
structure which interferes with the structures that we are 
looking at. So vitreous ice is really an invention that came 
along in 1980.  

And then Dubochet discovered, along with his mentor, 
that the formation of crystalline ice can be prevented by 
substituting ethane for liquid nitrogen. So now we have this 
little vessel of liquid ethane suspended in a bath of liquid 
nitrogen. And when the grid with the sample on it is 
plunged in there, then the ice that is formed is glasslike, and 
hence vitreous. So it is a very simple concept, but it is an 
ingenious idea, and all of a sudden, there was a way of 
freezing the molecules as if they were in liquid water, they 
stayed in liquid water. 
 
 
 
 
 
 
 
 

Meet Dr. Joachim Frank, Nobel Laureate 

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