The Shaw Prize in Life Science and Medicine 2017 is awarded in equal shares to Ian R Gibbons, Visiting Researcher, Department of Molecular and Cell Biology, University of California, Berkeley, USA, and Ronald D Vale, Professor, Cellular and Molecular Pharmacology Department, University of California, San Francisco and an Investigator of the Howard Hughes Medical Institute, USA, for their discovery of microtubule-associated motor proteins: engines that power cellular and intracellular movements essential to the growth, division, and survival of human cells.
Animal and plant cells possess an elaborate network of cables and filaments that organize the cytoplasmic traffic of material with the precision of a well-engineered motorway. Some compartments of cells move over short distances on the range of microns whereas others, particularly in nerve cells, may traverse from the cell body to the tip of a nerve terminal, from millimeters to as much as many centimeters away. The first such filaments to be discovered are composed of a protein called actin, the same protein that provides the striatal structure of a muscle cell. Actin filaments slide past one another as the basis of muscle contraction powered by a motor protein called myosin. The action of the myosin motor to slide actin filaments was first described in muscle tissues back in the 1940s and was rediscovered in the 1970s as a basis for contractile events in all other cells that possess a nucleus, the eukaryotes. Eukaryotic cells also have another network based on a protein called tubulin, which assembles into a cylindrical cable called the microtubule. Microtubules represent the conveyor belt along which membrane compartments are moved over long distances in the cell and serve as the basis of the beating motion of cilia which line the surface of cells to promote fluid movement, for example in the blood vessels and intestines, and also the motion of flagella that propel single-cell eukaryotes in their fluid environments. Microtubules also organize the regular segregation and inheritance of chromosomes that duplicate, divide and then partition into daughter cells during cell division.
Ian Gibbons and Ron Vale discovered the two families of motor proteins, dynein and kinesin, that move particles and membrane compartments along microtubules, that promote the beating of microtubules within cilia and that move chromosomes back and forth as the hereditary material prepares for the division of the nucleus during cell division.
Gibbons used a simple enzyme assay, the hydrolysis of a high bond in the energy currency of the cell, ATP, to isolate dynein from the microtubule structure, the axoneme, of cilia from the single-cell eukaryote Tetrahymena. His elegant experiments showed that the enzyme activity of dynein is tightly coupled to the bending waves of axonemes, if he limited the ATP or if he limited the motion using viscous media. Perhaps the most breathtaking experiment from this early period was to demonstrate that dynein produces sliding of microtubules relative to their neighbours in the axoneme. When he digested the protein connections between the microtubules in axonemes and added ATP, he observed sliding of microtubules by light microscopy. Gibbons devoted the rest of his career to understanding how dynein works. He cloned and sequenced the dynein, which revealed that dynein is a particular type of ATPase with six linked domains in one polypeptide. We now appreciate that dynein activity contributes not only to the motility of axonemes of cilia and flagella, but also to all forms of intracellular transport including chromosome segregation during cell division
As a very young scientist, Vale discovered kinesin, the third cytoskeletal motor protein. His discovery opened a biologically important field of research that has flourished over the subsequent 30 years, resulting in more than 6000 papers in the literature.
Having opened this field of research, Vale attacked the central question of how these motors work. He showed that kinesin walks processively along a single filaments of a microtubule, determined the first atomic resolution structures of kinesins (which revealed to great surprise ancient structural homology with myosin), determined one of the first atomic structures of dynein and carried out elegant single-molecule biophysics experiments to characterize the stepping behaviour of both kinesin and dynein.
Vale has also contributed in three significant ways to science education. He worked for several years as one of the directors of the physiology course in the Marine Biological Labs at Woods Hole, Massachusetts, USA. He has also taken that high-tech experimental approach to science pedagogy to India, where he and colleagues have run remarkable courses on modern light microscopy at Bangalore. Perhaps most impressive, Vale created an internet educational programme iBio seminar which has expanded with the broader ambition to cover all ages in the iBiology project.
The microtubule motors discovered by Gibbons and Vale lay at the heart of key aspects of human development and chromosome inheritance. Without these motors, the process of multicellular growth and division would be impossible. Indeed, diseases ranging from neuropathy, schizophrenia and neurodegeneration have been linked to the genes that encode these motor proteins. Once again, a discovery in basic science illuminates a fundamental property of cells so important to human health.
Life Science and Medicine Selection Committee
The Shaw Prize
17 June 2017 Hong Kong (Revised)
