An Essay on the Prize

Animals and plants possess an elaborate network of intracellular filaments that organize the transport of the cell’s building blocks with the precision of a well-engineered motorway. Some cargoes being transported within cells move over short distances (a millionth of a meter) whereas other cargoes, particularly those in nerve cells, must traverse distances as large as a meter from the cell body to the tip of a nerve terminal. All of this transport is produced by molecular motors, proteins that themselves are less than one ten millionth of a meter in size.

The first such molecular motor system was discovered in muscle. The filaments are composed of a protein called actin. During muscle contraction, actin filaments slide past one another, powered by a motor protein called myosin. This action of myosin was first described in muscle tissues in the 1950s and was discovered in the 1970s to power contractile events in non-muscle cells as well.

Eukaryotic cells also have another type of filamentous network composed of a protein called tubulin, which assembles into cylindrical tracks called microtubules. Membrane compartments and other cargoes are moved long distances along microtubules inside of the cell. Microtubules and their associated motors also provide the basis of the beating motion of cilia, such as those found in the cells lining the respiratory tract, or in the flagella, which propel sperm in their fluid environment. During cell division, microtubules and motor proteins also organize the segregation of chromosomes, the hereditary material that duplicates and then partitions equally into the two daughter cells.

Ian Gibbons and Ron Vale discovered the two families of microtubule motor proteins – dynein and kinesin. Humans have more than sixty genes encoding different dyneins and kinesins that generate all of the forms of motility described above and many more. These motors are essential for all eukaryotic life.

In order to isolate dynein from the single-cell eukaryote Tetrahymena, Gibbons used an enzyme assay that measures the hydrolysis of ATP, the chemical energy source used by molecular motors to power motion. His elegant experiments showed that the enzyme activity of dynein is tightly coupled to the bending waves of axonemes, the microtubule structure that comprises cilia and flagella. Perhaps the most breathtaking experiment from this early period was the demonstration of dynein-driven sliding of neighbouring microtubules within the axoneme after solubilizing the membrane and adding ATP. Gibbons devoted the rest of his career to understanding how dynein works. He cloned and sequenced the dynein gene, which revealed that dynein is an unusual 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 membrane transport and chromosome segregation.

As a very young scientist, Vale developed ways of studying, in a test tube, the intracellular transport system of nerve cells. These new motility assays led to the discovery of kinesin, the third type of 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 developed single molecule assays for kinesin and dynein that showed how these motors walk along a microtubule. Vale and colleagues also determined the first crystal structures of kinesin (which revealed to great surprise ancient structural homology with myosin) and dynein. He also uncovered how ATP hydrolysis leads to structural changes in these motor proteins, which drive motion and force production.

Vale also has contributed in significant ways to science education. He co-directed the Physiology Course at the Marine Biological Labs at Woods Hole, Massachusetts. He has advanced science education and culture in India, where he has founded an annual light microscopy course, an annual meeting for young scientists, and a website and organization for Indian biologists (IndiaBioscience). Perhaps most impressive, Vale created a free, online educational programme called iBiology. iBiology, whose videos are viewed in 175 countries, has the future ambition of explaining scientific discoveries to the general public.

The microtubule motors discovered by Gibbons and Vale lie at the heart of key aspects of human biology. Without these motors, embryonic development, cell division, and the function of the nervous system and other organs would be impossible. Indeed, diseases ranging from neuropathy, neurodegeneration, kidney disease, developmental disorders and infertility have been linked to genes that encode these motor proteins. Once again, a discovery in basic science illuminates a fundamental property of cells that is so critical to human health.

26 September 2017   Hong Kong