From the scientist’s view: a conversation with… David Barford
David Barford is a Group Leader in the Structural Studies Division at the LMB.
He received an undergraduate degree in Biochemistry from the University of Bristol and then completed a D.Phil at Oxford University under the supervision of Louise Johnson.
David has had a full career including working at Dundee University as a postdoc, then joining the Cold Spring Harbor Laboratory in New York State where he completed a three-year Fellowship, then returning to Oxford University as a lecturer. Whilst at Oxford, David also became a Fellow of Somerville college for five years. David then stepped back from teaching to focus purely on research at the Institute of Cancer Research in London.
David joined the LMB as a Group Leader in 2013, and became Head of Division for Structural Studies from 2015 until October 2024. His work focuses on how chromosomes are separated during cell division. David’s group uses electron cryo-microscopy to study the structure of protein complexes and machines which are involved in regulating cell cycle processes, and also chromosomal segregation at mitosis.
We recently spoke to David about his research and career in science. Here are some of the interview highlights, or scroll to the bottom of the page to find the full video.
What has been the most exciting thing about your research?
The most exciting finding recently of our research has been the understanding of how the kinetochores interacts with the DNA. The role of the kinetochores is to attach chromosomes to microtubules, and to withstand the pulling/pushing forces during mitosis. So how does the kinetochore act as this load bearing element to ensure that it remains attached to the chromosome during this mitotic event?
It was known that the centromeres, which are the loci on the chromosome which binds to the kinetochores, are defined by a specific nucleosome called the CENP-A nucleosome. Previously, people thought that the way that the kinetochore interacts with the centromeres is by recognising the CENP-A nucleosome that would be the anchor point by which the kinetochore would interact with the centromere.
But we found that the way that the kinetochore binds to the chromosome is simply by interacting with DNA. DNA is passed through a tunnel through the entire kinetochore complex. The complex actually surrounds the DNA like a like a hand holding a rope. You can see that that would provide a very strong, robust load bearing structure to allow the microtubule to pull on the kinetochore but also remain attached to the DNA. So that was a surprising result we had recently.
Has there been a pivotal experiment or moment that really moved your research and understanding forward?
The pivotal development in research recently has been the resolution revolution, in electron cryo-microscopy (cryo-EM), which has been driven by scientists at the LMB. One of the main reasons I moved to the LMB was to take the opportunity of using this sort of revolutionary cryo-EM to understand the structure of proteins.
This method allows us to understand the structures of very large complexes, which are very dynamic and unable to crystallise. Prior to cryo-EM, the technique to determine a structure was to crystallize it. But that’s actually very difficult when you have very large or very low abundance complexes which are very dynamic. Whereas with cryo-EM, it does not require crystallization. You can look at single particles and then determine all the different heterogeneity, confirmation and composition of these complexes. That really did push my research forward dramatically, and it allowed us to determine the structure of the anaphase promoting complex/cyclosome (APC/C) complex very quickly. We thought we might spend 10 years or more years on that project, but we finished everything in about three years. That was a huge development in structural biology.
What scientific breakthrough would you most like to make?
In terms of my own research area, I would like to understand the structure of the kinetochores inside cells. Currently, our approach is to reconstitute the kinetochore complexes in vitro using systems to understand single particles, and then using cryo-EM. But we want to understand the structure of the kinetochore bound to centromeres inside the cell. Centromeres of the human chromosomes are a very homogeneous repetitive structure; we know the structure of one of these repeats from our in vitro reconstitution experiments. We have no idea about how all these repeats are assembled inside the cell in the chromosome. To understand this, we need to use electron cryo-tomography (cryo-ET), which is a means to visualize structure of cells in the cellular context. That’s our current research activity of next five years.
Is there a part of your job that might surprise people?
I think what is expected is the transformational science of last sort of 25/30 years is how technology has really advanced to a point where we can do different science now. When I was doing my Ph.D., we had to do much more manual work, including data collection: we used films to collect the X-ray data, manually writing the number on the film, and then used film developer and fixer and then dried them. But now it’s on detectors and computers. Technology has really made a big impact on science. It’s not predictable how technology evolves. Is so much, especially now, machine learning, artificial intelligence, and that’s having a big impact on science. 30 years ago, I would not have dreamt that we would be able to do what we can do now, and do such large complexes in vitro and also in situ. That’s been the big unexpected development in my field.
David was interviewed for the LMB Alumni Newsletter on 6th November 2024