Prof Bill Earnshaw
FRS, FRSE, FMedSci
William C. Earnshaw completed his Ph.D. with Jonathan King at MIT in 1977. Postdoctoral training in Cambridge with Aaron Klug and Ron Laskey and Geneva with Ulrich Laemmli was followed by 13 years at the Johns Hopkins School of Medicine in Tom Pollard’s Department of Cell Biology and Anatomy. In 1996 he moved to Edinburgh as a Wellcome Trust Principal Research Fellow as part of the initiative to bring modern Cell Biology research to Edinburgh. He continues to hold that fellowship today. For more about Bill’s career click here.
Bill Earnshaw’s primary goal throughout his career has been to understand how chromosomes are compacted and segregated when cells divide. He began by studying DNA packaging in bacteriophages, but then moved on to the study of mitotic chromosomes in vertebrate cells. Discoveries from the Earnshaw Lab have led to fundamental breakthroughs in the study of mitotic chromosome formation, kinetochore structure and function and in the mechanisms of apoptotic execution. The Lab’s discovery of the chromosomal passenger proteins and their role in the integrated control of chromosomal and cytoskeletal events during mitosis revealed a previously unsuspected aspect of mitotic regulation.
Principal achievements of the Earnshaw Lab include the following:
- Combining small-angle x-ray scattering with conventional electron microscopy and computer modelling, Bill developed the first detailed model for the organisation of DNA packaged within the heads of double-strand DNA bacteriophages. This was confirmed 30 years later by others using cryoelectron microscopy.
- Bill’s biochemical analysis of the mitotic chromosome scaffold identified key components, including DNA topoisomerase II, SMC2 and KIF4. Later genetic studies by lab members Damien Hudson, Paola Vagnarelli and Reto Gassmann revealed that SMC2 is a key architectural factor in mitotic chromosomes and provided important insights into regulation of the still mysterious factor(s) that condenses the chromosomes in mitosis.
- Bill pioneered the use of autoantibodies for identification and cloning of key chromosomal proteins. His identification and cloning of human centromeric proteins using serum from a scleroderma patient was the breakthrough that opened the way for the molecular characterisation of the metazoan kinetochore. He holds two patents for the use of cloned autoantigens as immunodiagnostics.
- Discovery of INCENP by Carol Cooke led Bill and Becky Bernat to propose the first integrated control mechanism for the spatial and temporal coordination of chromosomal and cytoplasmic events in mitosis by chromosomal passenger proteins. Later biochemical studies by lab members Richard Adams, Sally Wheatley, Ana Carvalho and Reto Gassmann led to identification of the chromosomal passenger complex (CPC), containing Aurora B kinase plus its targeting and regulatory subunits INCENP, Survivin and Borealin/Dasra B. Studies of the CPC are now a core aspect of mitosis research.
- Biochemical studies of chromatin condensation in vitro by Eddie Wood led Yuri Lazebnik to develop the first cell-free system to study chromatin condensation and other nuclear events during apoptosis. This led to the first discovery and mapping of caspase cleavage sites, paving the way for detailed biochemical studies of apoptotic execution.
- While sitting in the audience at an EMBO Workshop in Heidelberg, Bill designed a synthetic DNA array that in collaboration with Vladimir Larionov and Natalay Kouprina (NIH, USA) plus Hiroshi Masumoto (Kazusa Institute, Japan) was used to obtain the first synthetic human artificial chromosome. This alphoidtetO chromosome has a kinetochore whose activity can be modulated by engineering its chromatin environment. It is being used to study the role of chromatin modifications and RNA transcription in the maintenance and assembly of the vertebrate kinetochore
- Shinya Ohta performed the first comprehensive proteomic analysis of vertebrate mitotic chromosomes in a collaboration with Juri Rappsilber’s group, identifying >4000 proteins and determining the number of copies of each per cell. To analyse the data, the two labs developed MultiClassifier Combinatorial Proteomics (MCCP) a multidimensional analyses that allows the identification of groups of proteins that co-vary in response to various biochemical and genetic treatments. This analysis was used to predict the function of novel proteins, including members of the Ska complex.
- Paola Vagnarelli in collaboration with Dan Booth showed that the famous cell proliferation marker protein Ki-67 is a protein phosphatase I-targeting protein that is required for a large number of nucleolar proteins to coat the surface of the condensed chromosomes during mitosis. This Ki-67 layer helps to keep chromosomes separate from one another in the crowded mitotic cytoplasm. The layer is known as the chromosome periphery compartment. Later, using SBF-SEM/CLEM (serial block-face scanning electron microscopy/correlative light-electron microscopy), Dan found that the chromosome periphery compartment rich contributes >30% of the total metaphase chromosome volume – much more than expected.
- Oscar Molina discovered an important function for mitotic transcription at centromeres. Transcription accompanied by increased centromeric acetylation of histone H3 on lysine 9 apparently resists encroachment of heterochromatin (which requires histone H3 to be methylated on lysine 9). Oscar did this by developing an “in situ epistasis” system to simultaneously target competing chromatin-modifying activities, thereby creating synthetic chromatin states on the tetO array of the alphoidtetO human artificial chromosome (HAC).
- In an interdisciplinary collaboration with the laboratories of Job Dekker and Leonid Mirny and using a system for synchronous mitotic entry developed by Kumiko Samejima, the team explored the roles of condensin I and condensin II in mitotic chromosome formation. This study used a combination of chemical biology, gene targeting, Hi-C genomics and polymer-modelling. The results revealed that interphase higher-order chromatin organisation disassembles during prophase as nuclear condensin II forms a helical scaffold from which chromatin loops are extruded. Upon nuclear envelope breakdown, cytoplasmic condensin I accesses the chromatin, forming nested loops that give chromosomes their compact morphology. Kumiko, collaborating with Dan Booth also used acute auxin-depletion combined with SBF-SEM/CLEM to show that condensin (i.e. both condensins I and II) is essential for shaping mitotic chromosomes, but not mitotic chromatin compaction.
- Bill’s text book Cell Biology, co-written with Tom Pollard and illustrated by Graham Johnson, is used throughout the USA and Europe. A third edition was published in 2017.
The work of the Earnshaw lab has been characterised by an integrated multidisciplinary approach involving methods as diverse as small-angle X-ray scattering, computer modeling, light and electron microscopy, proteomics, synthetic biology and gene knockout/knockin technology. Many of Bill’s >288 refereed publications spanning the years 1973 to the present date have been highly influential. When his entire output of >353 publications is considered (excluding meeting abstracts), according to Google Scholar the publications have been cited >54,000 times – an average of 123 times each (h=116).
Bill is a Fellow of the Royal Society of London (2013), The Academy of Medical Sciences (2009), the Royal Society of Edinburgh (2002), the AAAS (2007) and a member of EMBO (1999). He was awarded the Gregor Mendel Medal of the Czech Academy of Sciences (2002), an honorary Doctorate of Medicine by Charles University, Prague (2009) and made an Inaugural Fellow of the American Society for Cell Biology (2016).