Microtubules and Microscopes: Exploring the Cytoskeleton

This post was contributed by Clare Sansom, Senior Associate Lecturer at the Department of Biological Sciences

"The binding site for End Binding protein 1 (highlighted in green) on the microtubule lattice at the corner of four tubulin dimers, visualised using cryo-electron microscopy" (Credit Cell by Maurer et al (2012))

“The binding site for End Binding protein 1 (highlighted in green) on the microtubule lattice at the corner of four tubulin dimers, visualised using cryo-electron microscopy” (Credit Cell by Maurer et al (2012))

Electron microscopist Carolyn Moores, the most recently appointed professor in the Department of Biological Sciences at Birkbeck, gave her inaugural lecture at the college on June 1.

Moores arrived at Birkbeck in 2004 to start her research group and has risen rapidly and steadily up the academic ladder ever since. Introducing the lecture, the Master of Birkbeck, David Latchman, explained that Moores’ CV stood out in every way; she was clearly as gifted a teacher and administrator as she was a researcher. Furthermore, as she has won several awards for science communication, he predicted that the audience would be in for a treat. We were not disappointed.

Educational journey

Moores began her lecture by saying that she would talk about three different things: her own career development; her group’s research into the structure and function of microtubules; and the advancement of women in science, a cause that is close to her heart.

She remembered that she had wanted to work as a scientist as soon as she knew what a laboratory was, and she started young, as an intern in a research lab at Middlesex Hospital while still in the sixth form. School was followed by a BSc in Biochemistry at Oxford and a PhD in John Kendrick-Jones’ lab at the world-famous Laboratory for Molecular Biology (LMB) in Cambridge. She then moved to work as a post-doc with Ron Milligan at the Scripps Research Institute in La Jolla, California, USA, and it was there that she began her studies on microtubules.

Coming to Birkbeck

The award of a David Phillips research fellowship in 2004 gave her the opportunity to return to the UK as an independent researcher. She explained that there were three reasons – or more accurately three people – that led her to choose to come to Birkbeck. Working in electron microscopy, she was inspired by the work of Helen Saibil, one of the UK’s principal exponents of that technique; she had known Nicholas Keep, then a lecturer in Biological Sciences, as a friend since her time at the LMB; and she knew that she would value the interdisciplinary working environment of the Institute for Structural Molecular Biology under the ‘inspired’ leadership of Gabriel Waksman.

Research into microtubules

Moores then moved on to discuss the main topic of her group’s research: the three-dimensional structure, function and role in disease of tiny cylindrical structures known as microtubules. These are one of the building blocks of the cytoskeleton, which forms a framework for our cells in the same way that our skeletons form a framework for our bodies. They are about 25nm in diameter, which puts them firmly into the ‘nano-scale’ of biology that is easily studied using electron microscopy.

There is a cytoskeleton in every living cell, and it, and the microtubules that form it, are involved in many important cellular processes including shape definition, movement and cell division. Diseases as diverse as cancer, epilepsy, neurodegeneration and kidney disease have been linked to microtubule defects. Understanding their fundamental structure and function, as Moores’ group aims to, should help in understanding these disease processes and perhaps also in developing effective treatments.

Microtubules are built up from many copies of a small protein called tubulin, which, in turn, is a dimer of two similar proteins called alpha and beta tubulin. These tubulin dimers make contacts with each other both head-to-tail and side-to-side to create the cylindrical microtubule wall, fuelled by energy derived from the molecule GTP. Each tubulin unit has a definite “top” and a “bottom” and, as the units are oriented in parallel, so has the complete microtubule.

Microtubules are dynamic structures; they continue to grow by the addition of tubulin units to one end as long as GTP is available, and then begin to unravel and shrink. This dynamism, which allows them to respond to the changing needs of the cell, is essential for their function in healthy cells. In particular, microtubules organise chromosome structures during cell division and are therefore necessary for cell proliferation. As cancer is a disease of uncontrolled cell proliferation, it is possible to imagine that a molecule that could specifically block microtubule growth and assembly in the nucleus might be useful as an anti-cancer drug.

Moores and her group are aiming to understand the process of microtubule growth at as high resolution as possible, using electron microscopy. Unfortunately, however, the most detailed images can only be obtained if the specimen is at very low temperatures (in so-called cryo-elecron microscopy) and using this means that the dynamics of the specimens must be “frozen” into a still image. While it is now possible to see the individual tubulin subunits in the static microtubule images, many details of their structure can only be inferred from computational analysis.

Understanding growth

Moores went on to describe one project in her lab in a little more detail. This was an investigation of the structure and role of proteins that bind only to growing microtubule ends, falling off when the growth stops. It is possible to obtain low-resolution images of microtubules in which these molecules have been made to fluoresce, so only growing microtubules are tracked.

In order to understand the growth process in detail, the group developed an analogue of the GTP “fuel” molecule which can bind to the tip of a microtubule that is extending but not break down to release its energy, so the microtubule does not in fact grow. This forms a static analogue of a growing microtubule that retains all the characteristics of the dynamic structure but that can be studied at low temperatures.

Images of this structure have shown that the end binding proteins bind at the corner of four of the tubulin units. They have explained a lot of the properties of growing microtubules, but there is still more to learn. A full understanding will need structures that are at even higher resolution, where the positions of individual atoms can be made out. Following many years of technical development, today’s most powerful electron microscopes are now making this possible.

Women in science

In the last section of the lecture, Moores left the topic of research to talk briefly about another of her passions: the promotion of women in science. She explained that although 65% of under-graduates in the biological sciences are now women, the proportion of women drops to 40% at any academic grade and 25% for full professors.

A study cited by the European Molecular Biology Organisation has suggested that the barriers for women scientists to progress are set so high that at the current rate of progress full equality would never be achieved. Birkbeck has signed up to the Athena SWAN Charter, set up to encourage higher education institutions to transform their culture and promote gender equality. She described her work with the Athena SWAN team that has so far resulted in the college gaining a bronze award as being as exciting as, but also as challenging as, her studies of microtubules.

Nicholas Keep, Dean of the Faculty of Science and, as Moores had stated, a personal friend, gave the vote of thanks after the lecture. He paid tribute in particular to her value as a colleague, her administrative skills, and the importance of her contribution to the college’s application for the Athena SWAN award.

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