Figure 1. Biological variations in cell size. Eukaryotic cells average 10–20 m in diameter, but the range to which cells grow is diverse. The cells in this figure are drawn close to scale to emphasize the size variations. A scale bar is drawn for comparison. Cell size is determined by a variety of processes. For granular megakaryocytes, large cell size is associated with multiple copies of the genome (polyploidy). Fat cells are large because they accumulate excess lipid. Other cells contain varying amounts of total biomass, mostly protein, while maintaining a diploid genome size (haploid in oocytes). Some of the largest cells in the body are neurons like Purkinje cells and motor neurons, which grow by increasing cell mass. Likewise, adult polyploidy skeletal muscle cells, depending on the muscle type, can grow to 10–100 m in diameter by increasing cell mass.

Figure 2. Growth signalling in eukaryotic cells. Within eukaryotic cells is an integration centre where intra- and extracellular growth signals converge. The central regulator of this centre is a protein called TOR. TOR senses the incoming signals and relays the growth message to the machinery that builds new protein. Since protein constitutes the majority of the biomass of a cell, building new protein is a major way that cells increase their size. Inputs to TOR are generated by nutrients such as amino acids, which serve as both building blocks for making protein and as signals that activate TOR, and glucose, which is the fuel for making cellular energy in the mitochondria. Signals directly from the mitochondria and ATP may also signal to TOR. Extracellular signals from growth factors, such as insulin and IGFs also control TOR by activating intracellular signalling pathways like the PI3K pathway. Once activated, TOR triggers protein synthesis by activating initiating factors, which catalyse the association of mRNAs with the ribosome, and by activating the ribosome directly. TOR also turns on genes that are important for making new protein. Starvation for nutrients, stress or the antigrowth drug rapamycin can block protein synthesis by inhibiting TOR.

Figure 3. Starvation can cause diabetes by reducing the mass of insulin-producing cells. Protein malnutrition diabetes is a condition caused by reduction in mass of the insulin producing -cells of the pancreas as a result of starvation. In laboratory mice, partial inactivation of the growth network by genetically inactivating one of the downstream effectors of TOR mimics the effects of protein starvation. These mutant mice have reduced levels of insulin. Consistent with low levels of insulin, pancreatic sections showing -cells from the islets of mutant mice are decreased in mass (right) compared to islets of normal mice (left). This condition is one example of the importance of maintaining proper cell size. Pancreas sections stained with haematoxylin and eosin. Bar, 50 m. From Pende D et al. (2000).

Figure 4. Cells must grow during every passage through the cell cycle. Newborn cells must grow in size prior to dividing so that cell size does not progressively decrease with each division. Cells generally grow in the G1-phase of the cell cycle by increasing the rate of protein synthesis. G1 growth is influenced by nutrients, growth factors and hormones. Once the appropriate cell size is reached, and signals are present that permit cell cycle progression, growth slows down and DNA synthesis begins in S-phase. Once the genome is duplicated and cells prepare for division, the full-sized mother cell will divide into two smaller daughter cells and the process is repeated. In yeast, intracellular mechanisms monitor size in G1, restraining S-phase until a critical size is attained. It is not known how animal cells maintain size control as evidence both supports and contradicts the existence of a size-monitoring mechanism.

Figure 5. Hypertrophy versus Hyperplasia. Organs, during normal physiological growth, or when challenged by a pathological condition, can adjust in size in order to adapt to the changing demands. Increase in organ mass can occur by increasing the number of cells in the tissue, which is defined as hyperplasia. However, adult cells in some organs no longer maintain proliferative potential, and for such organs, increasing cell size is the only way to increase organ mass. This is defined as hypertrophy. Other organs use a combination of hyperplasia and hypertrophy to build mass. The increased size associated with hypertrophy directly results from increased protein synthesis.

Figure 6. Effects of increased growth factor and hormone signalling on organ and organism growth in laboratory mice. (a) Skinned forelimb and hindlimb from a 6-month-old normal mouse (left) and a transgenic mouse (right) genetically engineered to express higher than normal levels of IGF-1 specifically in skeletal muscle. The transgenic mouse develops normally, but has dramatic hypertrophic muscles compared to the mouse expressing IGF-1 at normal levels. From Musaro A et al. (2001) (b) Both mice in this image are 2 months old, but the mouse on the left has been genetically altered to lack the normal regulatory systems to control growth. Compared to the normal mouse (right), this mouse has deregulated and overactive growth hormone and IGF-1 signalling, resulting in gigantism. From Metcalf D et al. (2000).