Cell division, growth and death are the most basic, fundamental features of biology. Whereas mechanisms controlling cell division and cell death have been long studied, research on cell growth started in earnest only relatively recently. Michael Hall’s work provided a turning point in our understanding of cell growth. In 1991, he discovered the highly conserved, nutrient-activated protein kinase TOR (Target of Rapamycin), and he subsequently elucidated its role as a central controller of cell growth. This led to a fundamental change in our current understanding of cell growth. It is a highly regulated, plastic process controlled by TOR-dependent signaling pathways. As a central controller of cell growth, TOR plays a key role in development and aging, and is implicated in various disorders including cancer, cardiovascular disease, allograft rejection, obesity, and diabetes.
The studies that led to the discovery of TOR began in the laboratory of Michael Hall in the late 1980s. The initial experiments focused on the mechanism of action of rapamycin, a natural bacterial product then being developed as an immunosuppressive drug. Hall, in his search for the cellular target of rapamycin, used yeast genetics, assuming that the target was conserved from yeast to human. He first isolated the yeast gene FPR1 encoding the prolyl isomerase FKBP. The mammalian equivalent of FKBP was known to be a rapamycin (and FK506) binding protein in vitro and thus possibly the rapamycin target in vivo. However, Hall found that deletion of the FPR1 gene in yeast did not mimic the cell inhibitory effect of rapamycin treatment, suggesting that the FKBP protein was not the relevant rapamycin target in vivo. He next selected yeast mutants that were resistant to the antifungal effects of rapamycin. This yielded mutants defective in FPR1 and two new genes he named TOR1 and TOR2. Genetic analyses and concurrent studies by the chemist Stuart Schreiber revealed that although FKBP is not the relevant target for the inhibitory effect of rapamycin, it is a co-factor/receptor required for drug action. Rapamycin acts by forming a complex with FKBP and this complex then inhibits something else required for viability. This is now known to be the conserved mode of action of rapamycin in all eukaryotes. The genetic analysis also suggested that the relevant target is the product of the TOR genes. The Hall lab subsequently cloned and sequenced the two TOR genes, showing that they encode two highly homologous kinases.
Knockout of the TOR genes caused loss of viability and mimicked rapamycin treatment, confirming that the TOR proteins are the relevant target of rapamycin in vivo. Sequencing of the rapamycin resistant TOR mutant alleles revealed that the mutations in TOR invariably affect the same residue. These mutations prevent binding of FKBP-rapamycin to TOR without otherwise affecting TOR function. Throughout 1994 and 1995 TOR was identified in other species and these studies showed that TOR is indeed conserved from yeast to human, as originally presumed by Hall when he decided to exploit yeast genetics to search for the drug target.
Michael Hall next focused on elucidating the cellular function of TOR. He first mistakenly thought that the cellular role of TOR was to control cell division, based on the G1 phase cell cycle arrest caused by rapamycin treatment or knockout of the TOR genes. However, there was no obvious direct role for TOR in the regulation of cell division. At this time, Hall made another important discovery: TOR controls cell growth (increase in cell size/mass) in response to nutrients. There was at first confusion in the community regarding this discovery, for two reasons. First, the term "growth" was used at that time to refer to cell division (increase in cell number) rather than an increase in cell size. Second, it was thought that growth (increase in cell size/mass) was a passively regulated, spontaneous process, and thus did not have an underlying regulatory system. Hall redefined the term "cell growth" and argued that growth is in fact actively regulated, and that TOR is the central component of cell growth control.
In 1991, the first (and single, at that time) article on TOR was published, there are now >3000 publications per year on TOR. Thus, the discovery of TOR and its role as a central controller of cell growth was transformative. It changed our understanding of the fundamental process of cell growth and of many important growth-related physiological processes at the molecular level (e.g., nutrient sensing, muscle growth, memory and learning, aging, cancer, etc.). It also elucidated the mechanism of action of rapamycin.
Michael Hall went on to make other discoveries, in particular on how TOR controls cell growth. He showed that TOR signals through two separate signaling pathways to control several anabolic and catabolic processes which collectively determine mass accumulation and thereby cell size. The next major advance in the TOR field came in 2002, when Hall discovered two functionally and structurally distinct TOR complexes that he named TORC1 and TORC2. He then showed that the two complexes corresponded to the two previously identified TOR signaling pathways. This was a major advance because it provided a molecular basis for the complexity of TOR signaling. Michael Hall also started to work with mammalian cells and showed, along with others, that the two TOR complexes are conserved in mammals (mTORC1 and mTORC2).
During the last ten years it has also become apparent that mTOR signaling plays a prominent role in aging and a wide variety of diseases characterized by ectopic cell growth (e.g., cancer) or metabolic imbalance (e.g., diabetes). The early work by Michael Hall has expanded the TOR field to a large area comprising basic and medical research, and the pharmaceutical industry. Remarkably, Michael Hall is not just the founder but has remained the leader in this highly competitive field for over 25 years. His current work continues to focus on mechanisms of mTOR signaling, but is also elucidating the roles of mTORC1 and mTORC2 in metabolic tissues and in tumors. The aim of the work on metabolic tissues is to understand how mTOR controls whole body growth and metabolism. The aim of the tumor work, in mice and humans, is to understand mechanisms of tumorigenesis and evasive resistance to targeted cancer therapies. In summary, Hall's studies on TOR elucidated fundamentally and clinically important biology.