Grant: Project Grant

A central and longstanding problem in biology and biomedicine is the deceptively simple question: how do cells establish and maintain the constant size that is characteristic of each tissue in the body? Despite the study of this problem for over 100 years, we still do not understand how cells determine their size. Complex networks of molecular interactions ensure that the many trillions of cells that make up our bodies divide at the appropriate time. This "decision to divide" depends on the growth of cells to an appropriate size, termed the cell size threshold. The threshold appears to operate in all eukaryotic species, from yeast to humans. We have used the simple single-celled yeast as model to identify hundreds of genes that control size. We have found that the machinery that produces the proteins in the cell (the ribosome), the organelle that produces energy for the cell (the mitochondrion), the organelle that degrades and recycles cellular components (the vacuole) and the system that generates membranes and secretes proteins (the endoplasmic reticulum) are all critical regulators of cell size. However, it is not known how all these processes are coupled to the division machinery to set the size threshold. We will now use systematic functional genomic approaches to investigate how these size control networks operate in yeast as a simple model, and we will use this knowledge and advanced genetic and biochemical methods to decipher how the analogous processes work in human cells. The coupling between cell growth and cell division goes awry in many human diseases including diabetes, mitochondrial disorders, cancer and aging. Once we understand growth and division, we will be in a position to devise means to identify and ultimately correct the defects that underlie these and other diseases.