The Oxford Science Lecture Series

Professor  Petra Fromme

University of Arizona

“A New Era in Structural Biology”

 Dorothy Hodgkin Memorial Lecture 2015

University Museum, Oxford, 12th March 2015

Femtosecond crystallography opens a new era in structural biology; the story of missions impossible, from penicillin to Star Wars in crystallography.

The 2015 Dorothy Hodgkin Lecture was given by Prof. Petra Fromme from the University of Arizona. Professor Fromme studied Biochemistry at the Free University in Berlin. She did her PhD in Chemistry at the Technical University in Berlin and became an Associate Professor there before taking a Chair at the Arizona State University in 2002. In August 2014 she was appointed to lead a new Biodesign Institute Initiative, the Centre for Applied Structural Discovery, that will have a significant impact on the fields of bioenergy, enzyme catalysis and drug design.

Prof. Fromme began her talk by discussing how Dorothy Hodgkin had been fascinated by growing crystals from a young child. She said that she was envious of Dorothy, whose mother had encouraged her to do science, because when she was growing up she was supposed to study needlework rather than woodwork. Dorothy’s mother had given her a book by William Bragg entitled ‘Concerning the Nature of Things’ for her 14th birthday and Dorothy subsequently became only the 3rd female student to study chemistry at Oxford. As we know, she went on to win the Nobel Prize for Chemistry, the third woman to be given that award. Prof. Fromme commented that, depressingly, there has only one woman to win the Nobel Prize for Chemistry since then, Ada Yonath, who received it for studies of the structure and function of the ribosome.

Since the early work in crystallography, by Dorothy and others, 100,000 protein structures have been determined, but of those only 550 are membrane proteins and fewer than 50 are from large complexes. Prof. Fromme commented that these form the latest challenge, saying that, as nature is dynamic, it would be wonderful to be able to visualise structural transitions and make movies of proteins moving as ligands bound. To do this one needs a femtosecond laser (much more powerful that Darth Vader’s light sabre!)

Photosynthesis transformed our planet, 2.5 billion years ago, but the energy generated and stored is rapidly being used up as fossil fuels are burned. Prof. Fromme has been studying a complex called photosystem 1, which is the largest and most complicated membrane system studied so far. It has taken 13 years to solve the structure as the crystals contain 75% water and can be destroyed very easily. Traditionally, crystallography has required large crystals to solve structures, but if one could study nanocrystals then that would open up the possibilities for studying molecules which are not stable as larger crystals. In 2000 it was proposed that, if one could make an x-ray beam with 1012 times the current energy, one could get images from tiny crystals before they were destroyed by the beam. Prof. Fromme and her team of physicists submitted multiple grant applications for this project, which were all rejected as being ‘impossible’. They decided to proceed anyway and built the laser. The physicists wanted to start by testing a crystal of lysozyme but Prof Fromme persuaded them to let her start with photosystem 1 – and they saw beautiful diffraction patterns - when, later, they looked at lysozyme it didn’t work! They also saw ‘fringes’ which had been predicted many years before but never seen, and which can give valuable information about the size of the crystal. Using this laser, 15 structures have been solved, and published in Science or Nature, over the last 3 years.

The challenge now is to observe dynamic systems. Prof. Fromme wants to be able to visualise how photosynthesis harnesses energy. Using femtosecond nanocrystallography they took multiple images of another complex, photosystem II, which is at the beginning of the chain of molecules which convert light to energy. They hope to see the changes in structure over time and to understand how the energy is generated. Unfortunately, there are only two high energy laser systems in the world, and so there is limited time available for these complicated experiments. The solution would be to design a smaller, more economically viable system to generate femtosecond lasers, and Prof. Fromme and her team are now doing this, reducing the cost from $1.5 billion to $20 million! She described this transition as being equivalent to the transition in technology between the computers used by Dorothy Hodgkin 50 years ago, to those we use routinely today. She has been awarded a grant of E14 million by the EU and proposes that in 10 years’ time there should be beam time available 24 hours a day and will be able to get movies of complex structures routinely! If anyone can do that, it is this amazingly dynamic scientist who has achieved so much already!

The evening concluded with questions, after which the audience and speaker enjoyed a glass of wine in the gallery of the museum.  

Dr Carolyn Carr, Cardiac Metabolism Research Group, University of Oxford.