Slide courtesy of Stephanie Buvelot
Among his many contributions, Dr. Lee Hartwell's crowning achievement was to show that it is possible to use genetics to understand the cell-division cycle.
Lee chose the yeast Saccharomyces cerevisiae as a model because it undergoes easily visualized morphological changes as it progresses through the cell cycle.
This enabled Lee to isolate a collection of cell-division cycle mutations that prevented progression through specific parts of the cell cycle. His collection of cell-division cycle mutants has proved to be an invaluable treasure for the cell-cycle field. This class of mutants contains essentially all of the critical regulators of cell-cycle progression.
Perhaps most remarkable is that these genes - and the pathways they control - were highly conserved during evolution. The cell-division cycle genes have counterparts in all nucleated organisms and are the key regulators of cell proliferation in species ranging from yeast to humans.
The fundamental insight to emerge from Lee's initial experiments was the idea that key cell-cycle events could be grouped into dependent, genetically definable pathways. Thus, the occurrence of specific cell-cycle events requires the prior completion of other, earlier events.
Most influential was the concept of START, the point at which the cell enters the division cycle after responding to both internal and external cues.
Lee recognized START to be the crucial point at which cell division is integrated with extracellular and intracellular signals, a concept that extends to all nucleated organisms and is critical to understanding the unconstrained growth characteristic of tumors.
Most remarkable is that Lee identified a gene known by scientists as CDC (cell-division cycle) 28, which controls START. This major discovery formed the basis for enormous advances in understanding the cell cycle that have been made during the last 15 years.
Initially, it was thought that the dependent relationships among cell-cycle events could be explained if a late event required a product produced by an earlier event. Lee's most recent studies have shown that dependencies can be established in an entirely different way, through the operation of cell-cycle checkpoints.
Lee showed that early cellular events send a signal that prevents the initiation of later events. Mutations in checkpoint pathways allow late events to begin even if early ones have not yet been finished.
Lee pointed out that checkpoints guarantee the integrity of the cell-division cycle by allowing the cell cycle to halt and repair processes to operate before errors in cell duplication are passed on to daughter cells.
The defining characteristic of a tumor cell is its genetic instability, and Lee proposed the importance of checkpoint abnormalities in understanding tumor-cell biology and in formulating new strategies for drug discovery and therapy.
Lee discovered that yeast responds to DNA damage by temporarily arresting progression through the cell cycle. This checkpoint response permits the repair of DNA damage that would otherwise lead to cell death or inheritance of altered genetic information.
Checkpoints are now known to operate at multiple key transitions in the cell cycle, safeguarding against deleterious events that would arise if cell-cycle progression continued without correction of genetic errors.
One of the more important outcomes of this work has been new insight into the function of genes known as tumor-suppressor genes.
These normally perform checkpoint functions during the cell cycle. Loss of their function in tumor cells causes genetic instability and rapid evolution of increasingly malignant tumor types.
Cell duplication requires the interactions of thousands of molecules and the operation of countless biochemical pathways.
How are these processes coordinated with one another to allow precise duplication of the cell? Is it even reasonable to imagine that one could discern and explain the underlying logic of such a complicated array of events?
In the 1960s, when Lee began his study of the cell cycle, he reasoned that the events of the cell cycle were under genetic control and that it would be essential to study these events in an organism such as yeast.
This insight led to the profound discoveries described above and has spawned the development of research programs throughout the world.
In multiple instances, Lee's contributions have opened new fields, provided the foundations for the work of numerous other laboratories and have offered an insightful framework within which to interpret his own work and the contributions of others.
For example, isolation of the cell-division cycle mutants provided a rigorous definition of multiple important steps in the cell cycle and opened the way for Lee and many others to identify, isolate and determine the function of the genes involved in the control of the cell cycle.
The insights that led to the definition of START, and later to the existence of checkpoints, were major conceptual advances that now guide the cell-cycle field.
Lee initiated another important field of research with his development of a simple color assay for chromosome loss.
This development led him to define and analyze several genes involved in chromosome stability. It also initiated work by others in defining the roles of chromosome elements (centromeres, origins of replication and telomeres) in maintaining chromosome stability.
Lee's latest and perhaps most exciting contribution is the realization that cancer cells bypass cell-cycle checkpoints. This insight has provided a framework to think about the relations among cancer, chromosome instability, genetic loss and DNA damage.
Most exciting is that this insight has led Lee to propose practical ways in which yeast might be used to screen for novel anti-cancer drugs. Any one of these observations/insights is deserving of an award in itself.
Modern era of studies
In essence, Lee deserves credit for initiating the modern era of studies into the cell cycle.
For more than 30 years, he consistently has contributed experimental and theoretical insights in this field.
The completeness of his work is exemplified in his profound theoretical insights, the creative yet simple design of experiments and the remarkable observations that led to the definition of important interactions among components of the cell-cycle machinery.
The widespread application of his body of work in virtually every yeast laboratory, as well as in laboratories attempting to extend Lee's observations to higher organisms, cannot be overstated.
No single investigator, other than Lee, has made the seminal contributions that form the foundation of our current understanding of the cell cycle.
His contributions also have been seminal to much of our current understanding about the molecular basis of cancer, and he is now attempting to apply these discoveries to finding novel agents for the treatment of cancer.