Better Living through Cell Death: HHMI's Herman Steller on Apoptosis

The protein it expresses is a caspase?

It's a caspase-activating protein. The caspases are made as inactive pro-enzymes, so they are not yet active. They are made in the cell but remain in a dormant stage until they are converted to an active protease. And this conversion process is blocked by the IAPs, the "brake on death" that I mentioned before. The IAPs make if very difficult to activate capases, and in this way provide a safeguard against the accidental death of cells that should live. Reaper, grim, and hid remove this brake, like keys unlocking a door to a dangerous beast restrained behind it.

High-Impact Papers by Herman Steller,
Published Since 1993
(Ranked by average citations per year)

Rank	Paper	Total Citations	Average cites per year
1	H. Steller, "Mechanisms and genes of cellular suicide," Science, 267(5203):1445-9, 1995.	924	205
2	K. White, et al., *"Genetic control of programmed cell death in Drosophila,"* Science, 264(5159):677-83, 1994.	253	46
3	M.E. Grether, et al., *"The head involution defective gene of Drosophila melanogaster* functions in programmed cell death,"** Gene. Dev., 9(14):1694-1708, 1995.	99	28
4	J.M. Abrams, et al., *"Programmed cell death during Drosophila* embryogenesis,"** Development, 117(1):29-43, 1993.	170	26
5	K. White, E. Tahaoglu, H. Steller, *"Cell killing by the Drosophila* gene reaper,"** Science, 271(5250):805-7, 1996.	88	25

SOURCE: ISI’s Personal Citation Report, 1981-June 1999.

What is the state of the research today?

That gets fairly detailed and complicated. An example of one of the things we can do is, just by expressing these genes, kill cells that would normally live. We can turn on reaper by introducing a protein that will activate the death program in such cells. Another thing we’ve shown is that the hid protein is inactivated by the ras pathway. The ras pathway receives a lot of attention because of the important role of ras as an oncogene. Initially it was shown that ras activity can drive cells into proliferation, but ras can also block apoptosis. We published a paper in late 1998 in Cell showing that ras promotes cell survival in Drosophila because it leads to the phosphorylation of hid via MAP kinase and the phosphorylated hid is inactive. It’s not a killer anymore. This is a somewhat sophisticated pathway to control death. It also explains why ras is such a powerful oncogene. It can both promote cell proliferation and block apoptosis. And that dual effect makes it a very powerful transforming oncogene. Those are just a few of the connections we’ve been able to discover.

Are there clinical implications?

A while back we published a paper in Nature showing that inhibition of cell death can really lead to the rescue of cells that continue to function. We looked at a model for retinitis pigmentosa, a human degenerative disease that results in progressive loss of vision. In many cases there are genetic components of this disease. It runs in families, and people have identified in many of these cases the molecular lesions that lead to the disease. Many mutations occur in the photo-pigment rhodopsin. These are usually not mutations that destroy the function of rhodopsin, but they cause the protein to function somewhat abnormally. The amazing thing is that Drosophila uses the same type of photopigment for visual transduction and the same point mutation that causes retinitis pigmentosa in humans causes a very similar disease in flies. So one of the things we investigated here was whether we could block death in the fly model of pigmentosis, and whether blocking death would lead to retention of vision in such flies. In other words, could we prevent them from going blind?
We showed that if you block apoptosis in the retina of such mutant flies the cells will no longer die and, more importantly, the cells will continue to function. They will not be perfect, but they will mediate very robust vision. So the speculation now is that the cells have a little defect, with mutant rhodopsin, and they realize that they’re not functioning perfectly and they kill themselves, even though they’re still capable of decent function. So if we prevent them from killing themselves, they can continue to function despite that insult. That finding has important implications because it says that if you could do that in a human with retinitis pigmentosis, or perhaps similar degenerative disorders, maybe cells could continue to function and the patient would benefit significantly.

To what extent would that apply to degenerative disorders like Huntington’s or Alzheimer’s?

That’s what remains to be shown, but I'm very optimistic. Especially for all acute diseases, maybe stroke, maybe heart attack, spinal cord injuries, including some chronic disease. There will be other diseases where blocking apoptosis won’t help because the cells have passed the point at which they still function. It has to be tested in all these cases. But I very strongly believe that there will be many diseases where blocking apoptosis will improve the condition of patients.

What about cancer therapy? That's where a lot of the apoptosis talk seems to lead.

Well, it should almost certainly lead to new opportunities in cancer therapy. I've talked about ras, for instance, and survival signaling involving social controls. Cancer cells have to break through that. They become independent of other cells providing them with survival signals. If we really understand well all the steps cancer cells take to reach that level, we might be able to reinstate the mechanism of cell suicide in cancer cells so that they kill themselves. There is some very exciting work going on in tumor suppressor genes such as p53 that seems to be just scratching the surface there. This kind of work has a lot of potential, a lot of promise to give us new ideas of how to kill cancer cells. Some of the basic science has real implications for therapies. A lot of things are moving now. It is really, really exciting.