In Vietnam, "we had to destroy the village in order to save it." Inapoptosis (programmed cell death), pulling the cells back from thebrink of suicide can lead to their un-programmed demise.
From alopecia (baldness) to Alzheimer's disease, apoptosis seems tobe the process that pushes cells to their self-inflicted death, in orderto save them from a fate worse than death. "Basically, any cancer cellis a cell that's failed to undergo apoptosis," observed biochemistAnthony Ford-Hutchinson vice-president of the Merck Frosst Centerfor Therapeutic Research in Quebec.
"Apoptosis," he told BioWorld Today, "is an extremely protectivemechanism. A good example would be sunburn. Damage to the cellsin the skin, potentially damaging to DNA, could obviously lead on toforming skin cancer. The way the body deals with that is by inducingapoptosis in those cells _ which in fact kills them off."
Conversely, Ford-Hutchinson pointed out, "In neurodegenerativediseases, such as Alzheimer's, Parkinson's and Huntington's chorea,the loss of neurons in the brain seems due to inappropriate apoptosisrather than necrotic events. Their DNA is nicked into a whole lot oflittle pieces." (See BioWorld Today, May 28, 1993; p. 1.)
Scientists at Merck Frosst's department of biochemistry andmolecular biology, who report to Ford-Hutchinson, have co-authoreda paper in today's issue of Nature, dated July 6. Its title:"Identification and inhibition of the ICE/CED-3 protease necessaryfor mammalian apoptosis."
Proteases trigger apoptosis, but what triggers proteases? Otherproteases. These cleave off the inactive "pro" or precursor segmentsof the trigger enzymes. As a can-opener releases food, they exposethe active component that turns on the death cells of apoptosis.
What the Nature paper reports is identification by Merck Frosst of aprotease that cleaves a specific enzyme, namely, poly (adenosinediphosphate-ribose) polymerase, better known as PARP. PARP isbest known as an apparent DNA-repair mechanic, called in by thebody to detect the nicks inflicted on the genome by environmentalstress.
The co-authors have nick-named their PARP-cleaving, apoptosis-inducing enzyme "apopain." It turns out to be the active form ofanother precursor cell-death instigator called CPP32, Ford-Hutchinson said.
"So you would expect," he observed, "that a key protease involved inapoptosis [i.e., apopain] would be able to disable various keyenzymes involved in DNA surveillance and repair [e.g., PARP]."
CPP32 in turn is most closely related structurally to the two path-finding enzymes of apoptosis research, the roundworm's CED-3 andthe human ICE _ interleukin-1b-converting enzyme.
Scientists at Vertex Pharmaceuticals Inc., of Cambridge, Mass., andat Yale University announced ICE last March. (See BioWorld Today,March 31, 1995; p. 1.) Merck Frosst regards Vertex as a frontalcompetitor, Ford-Hutchinson said.
As a wholly owned subsidiary of Merck & Co., of WhitehouseStation, N.J., Merck Frosst in Canada is pursuing potential ways ofintervening therapeutically in disease-associated apoptosis. "It's avery delicate system to want to interfere with," the research vicepresident observed. "I think it's a little too early to say at the momentwhat our intervention strategy will be."
Informally, Ford-Hutchinson added, "You could envisage that youmight want to acutely inhibit apoptosis, to prevent some of itsconsequences, in very acute situations, where any benefits outweighthe risks, for example in cerebral ischemia. Obviously, itsconsequences there are paralysis."
"From a pharmacological perspective," he continued, "our goal is toidentify if there are potential targets in there, which could be usedeither to control apoptosis, or _ I guess you could use these things asgene therapy agents _ for inducing programmed cell death as well,although that's a bit more long-term."
He also made the point that his apopain "is the most homologous toCED-3, the death gene in Caenorhabditis elegans. As this tinygarden-variety roundworm or nematode develops to maturity, it shedsor shucks many of its fetally-useful but now superfluous cells byexpressing its apoptotic gene, ced-3. This encodes the protein CED-3, which pushes the now-redundant cells over that suicidal brink. n
-- David N. Leff Science Editor
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