Cell death at a distance

Under certain circumstances including during development, large numbers cells kill themselves and it's clear that when one cell commits suicide, it can persuade other cells to follow suit, but how? Hermann Steller spoke to Chris Smith... 

Hermann -   My name is Hermann Steller.  I'm a Professor at the Rockefeller University in New York and also, an investigator of the Howard Hughes Medical Institute.  It's been typically considered that cells undergo apoptosis by themselves that they make the decision between life and death and then carry out this programme - cell death mechanism - to self-destruct.  And the current study actually shows that these cells are very active in influencing each other in their life and death decision.  Cells that die can still lead other cells to die as well.  This is significant because both in normal developments and in certain disease situations, large groups of cells die in a somewhat coordinated behaviour and the signal to die can be heard amongst the population and coordinated suicidal behaviours achieved, a little bit like lemmings, all jumping over the cliff.

Chris -   So, some kind of signal originates from a cell or group of cells that have become destined to die and other cells, what in the near vicinity die, or does this signal potentially work over longer distances?

Hermann -   Well, the surprising thing in the study was that the signal can work over considerable distances.  A group of cells in one place can signal many, many cell diameters away to another group of cells that it's time to die.  Now, I should say that initially, apoptosis has been seen as something where the only thing that the dying cell signals to environment as an 'eat me' signal so that the corpse is removed.  Subsequently, a number of labs have shown that cells, it can actually release signals to stimulate cell division.  That seems to make sense in a situation when a cell is lost that you want to replace.  So it's, "I'm dying.  Please replace me" signal.  So, in this context, it was very surprising that when there's a strong stress on a tissue that the dying cells can release signals that travel over considerable distances to stimulate more cell death.

Chris -   How did you actually discover this?

Hermann -   Well the post doc in the lab studied the signalling of dying cells in the developing drosophila wing.  He generated a strong cell death situation in one piece of the wing and then she saw to her surprise that in a region quite far remote that there was cell death at the distance.

Chris -   How did you find out that it wasn't just the fact that lots of cells were dying and there was some kind of necrotic effect if you've got lots of dead tissue, this might be inducing the death?  How did you prove there had to be some signal made actively and sent from cells that are destined to undergo apoptosis which was triggering other cells remote to die?

Hermann -   So, we use a system where we, on the one hand, induce cell death with key signalling molecules to activate cell death programme.  But then we can arrest the execution of cell death with an inhibitor of the proteases that are responsible to carry out cell death.  So, in this system, the cell basically thinks it's going to die, but it's prevented from carrying out the real destruction.  So, these are what we call 'undead cells'.  They are really cells that think in a way these cells are dying, but they stay alive.  As a result of that, these cells also signals for much longer, virtually indefinitely and allow us to look at the signalling context.  So, there's really no cell death and no tissue loss occurring but still, the phenomenon of inducing death at a distance is observed.

Chris -   So, you programme these cells to think they're dead, but they remain viable and pump out whatever the signal is.  You see corresponding death in other cells in other bits of the embryo.  So, how did you then track down what the chemical was that was doing that signalling?

Hermann -   We had reasons to suspect that two candidates signals.  One is the Jun Kinase pathway, the JNK, which has been implicated in signalling decisions in cell death and ligands with this pathway called eiger which is related to tumour necrosis factor conserved rodent skin, in both insects and in mammalian systems.

Chris -   How did you then explore what those were doing?

Hermann -   Well, we again could take advantage of the powerful genetic methodologies in drosophila to inactivate these pathways.  So very strictly, we just take away the gene that encodes eiger and then ask if we would stop this apoptosis, induced apoptosis.  Specifically, we were able, not just to remove eiger throughout the entire tissue, but we could specifically eliminate eiger function in the cells that would undergo apoptosis and that would completely abrogate the induction of apoptosis at the distance, even though these cells at a distance still have normal eiger function.  This really shows that it is eiger required in the dying cells as a signal to travel and induce apoptosis at a distance.

Chris -   But all around my body every day, there are billions of cells committing suicide in this way, so why don't I just unleash this dramatic domino effect of apoptosis and all my tissues self-destruct?  Something must be opposing the apoptosis induced apoptosis phenomenon.

Hermann -   Yeah, that's an excellent question and something where we really don't have very complete answers.  it's through that small amount of apoptosis will actually lead to a compensatory response where the dying cell stimulates growth and regeneration.  Only when there's sort of a large scale of death is apparently to signal strong enough to kill.  But there must be protective mechanisms because even in the systems we've studied, we've seen cells in between of being affected.  So, there's a different sensitivity that cells have and there must be a complex regulation to protect against the unwanted apoptosis induced apoptosis.