In 1988, an Australian group led by Suzanne Cory and Jerry Adams first published evidence that Bcl-2 regulates cell survival. That was a seminal finding (see D.L. Vaux, et al., Nature, 335(6189):440-2, 1988.) It showed that Bcl-2 was a gene associated with cancers that was not affecting cell division but rather cell life span. A number of us had done similar work at about the same time. But that group had the first clear demonstration of this gene's connection to cell survival.

   The Bcl-2 gene was actually cloned in ’85 or ’86 by Croce’s group, and then in '88 the Cory and Adams group published the first paper showing that it was linked to cell death–functioning as a survival gene. That marked a milestone in the field. At roughly the same time, two different groups of immunologists, led by Shigekazu Nagata and Peter Krammer, who were making antibodies against lymphocytes, discovered antibodies that triggered the death of the cells. This led to the discovery of a receptor named "Fas" that turned out to be a member of a larger family of death receptors–namely the TNF receptor family. The discovery of Fas sparked quite a bit of interest in the field because it provided the first example of a receptor system that was designed to program a cell to die.

   In parallel, hematologists working on various growth factors, cytokines, and so forth found that one of the important things these factors do is sustain cell survival. Thus, not only were these colony-stimulating factors, or CSFs, affecting cell division, they were giving quite important survival signals to the cells. This observation gave rise to the idea that there are hormone-like polypeptide factors secreted by cells that bind to receptors on target cells and which deliver signals necessary for survival. Researchers found that these factors suppress an endogenous death program within the cells. Thus, it became clear that these factors regulate cell numbers in the body by controlling cell life span.

   For example, some of this early work involved the hematopoietic system. When you get an infection, one of the things that happens is that your white blood cell count increases. Researchers found there are lymphokines and CSFs that bind receptors on the white cell precursors, causing them to proliferate and differentiate. However, not only are these factors instrumental in cell division and differentiation, but they also deliver essential signals for cell survival. If these cells did not have these signals, they would die. So that observation connected growth factors to this pathway as well, and suggested that, again, there’s some kind of active process here–that you need a factor to bind a receptor to send a signal into the cell to say "stay alive." Regulation of cell life span helps control the number of white blood cells, for example, during and following an infection. After the infection is cleared, the white cell count goes down again. It declines because the cytokines that were stimulating proliferation and survival of the white blood cells are no longer present. If you think about it conceptually, it just makes a lot of sense. It gives Mother Nature two ways of regulating the number of cells–controlling both the input and the output. Cell division is like the accelerator pedal of a car while cell death is like the brakes–you need both to be in control. Think of it like filling up a bathtub with water: the rate at which the tub fills is going to be dependent both on the rate at which water's coming in and whether you’ve got the drain open. So when cells are normally being produced, what we have is a situation where the drain is open, the water is on, but everything is being regulated so the amount of input equals the amount of output.

   In a typical day, an average adult will eradicate between 50 and 70 billion cells. In the course of a year that equates to a mass of cells almost equivalent to our entire body weight. Roughly a million cells are being produced and eradicated every second in our bodies.

   Not only can you explain a lot of normal physiological events through studying programmed cell death, but the process can go awry, resulting in either too little or too much cell death in many diseases. That’s one of the reasons why apoptosis has become such a hot field. This pathway is highly relevant to the vast majority of human diseases. In fact it’s estimated that 70 percent of all human diseases have an underlying problem in the regulation of this pathway.

   Defects in apoptosis regulation occur in cancer, where cells accumulate because they’re not dying as they should. In autoimmunity, defective apoptosis plays a role–often the problem is that the immune-cell education program is not working properly and autoreactive immune cells are not being eradicated by apoptosis. Plus, a wide variety of diseases can be attributed to inappropriate triggering of this pathway–for example, in stroke, heart failure, and HIV infection.

You’ve got to wonder how a complicated system like that ever got started.

   Reed: It may be an evolutionary adaptation to viruses. If a single virion binds to a cell and infects it, one of the best ways to ensure that the virus doesn’t contaminate the whole body is for that first infected cell to commit suicide before the virus can replicate. If you can trigger a cell-suicide mechanism early on, then the rest of the organism would be spared. This is one of the theories we’ve advanced as to why you can see evidence of active cell-suicide programs even in very primitive organisms.

   A further ramification of this concept is that if the viruses are to successfully overcome the tendency of cells to kill themselves, then viruses must create their own anti-death genes. So what you find is that viruses did in some cases, create their own anti-death genes, or more often, they stole them from animal cells that they had infected. This is what one sees with baculo viruses–the insect viruses that led to the discovery of the IAPs, or "inhibitor of apoptosis proteins." Initially IAPs were observed in insects and insect viruses, but then IAPs were discovered throughout metazoan species: in flies, mice, rats, and humans. What was unclear was how IAPs function. Some work that we did, spearheaded by Quinn Deveraux in our lab, resulted in the discovery that the IAP-family proteins directly bind to cell-death proteases that exist inside the cell. That's a "hot" paper that we’re particularly proud of (see Q.L. Deveraux, et al., "X-linked IAP Is a direct inhibitor of cell-death proteases," Nature, 388(6639):300-4; 1997.)

   We already knew that there was a family of cell-death proteases called "caspases" that are normally present in cells, but they’re lying in a latent, inactive form. What happens in apoptosis is that these proteases become active and start chopping certain proteins inside the cell, which leads to the cell's demise. What we figured out was that these IAP proteins were directly binding to these proteases and suppressing them. So they’re acting as endogenous, natural protease inhibitors.

   Another hot paper involves our studies of BCL-2 protein, which is a survival protein. Its mechanism or function had also been unclear. What was known was that this protein interacted with surface of mitochondria, the energy-producing organelles within the cell. Mitochondria perform many vital functions for the cell, but they also participate in cell death. BCL-2 actually interacts with the mitochondria, but it wasn’t clear how. One of the papers that was highly cited was based on work by Sharon Schendel in the lab. She showed that BCL-2 functions as a channel protein that inserts into the membranes and creates channels. This gave us some new insights into the mechanism of Bcl-2 (see S.L. Schendel, et al., "Channel formation by antiapoptotic protein BCL-2," Proc. Natl. Acad. Sci. USA, 94(10):5113-8, 1997). Similar findings have been reported by other groups who studied other members of the Bcl-2 family.

It must have been really interesting to be at the forefront as research in this field exploded over the past decade or so.

   Reed: Every year more and more of the dots and dashes get filled in, in terms of understanding the connecting pathways and understanding how each of the individual molecules that we and others have identified are connected to each other and to a whole orchestrated program. It was very exciting to watch it, and to be a part of it. It's a very exciting field, where there’s exponential growth in our acquisition of knowledge and understanding of this pathway. The other thing that’s been exciting is that a lot of this has happened at the same time that a wide variety of new technologies have emerged, making it easier to do research in general. The combination of new technologies together with the fact that this is a new field has allowed progress to be made very quickly. It’s been an exciting ride.