As apoptosis sets in, the cell shrinks, its nucleus shrivels, itscomponents break apart, and within hours it's dead.

Before a single cell can commit suicide for the greater good of itstissue, organ and body, something has to trigger that cell's decision toself-destruct. And something farther upstream in the programmed celldeath (PCD) cascade has to trigger that trigger. The initial apoptosisimpulse is a gene, or genes.

Sometimes, something along the domino-row of messages from geneto cellular victim can get hung up, so cells scheduled to die go righton living, and multiplying. Result: cancer.

Or else, the suicide signal may become jammed in the "on" position,and cells intended to stay alive perish prematurely instead. If theseinadvertent casualties are neurons, the result may be early-onsetAlzheimer's disease, or other central nervous system disorders.

This past week, scientists in Canada and the U.S. reported separatelythat they have discovered and isolated apoptosis genes with likelyconnections to diseases, notably Alzheimer's.

In the current Nature, dated Jan. 25, 1996, University of Ottawaresearchers Robert Korneluk and Alex MacKenzie announced"Suppression of apoptosis in mammalian cells by NAIP [neuronalapoptosis inhibitory protein] and a related family of IAP [inhibitor ofapoptosis proteins] genes." (This finding already has led to creationof ApoptoGen Inc. to commercialize the intellectual property it hasgenerated.)

A day later, in Science dated Jan. 26, 1996, immunologist andmolecular biologist Luciano D'Adamio, and his co-authors at theNational Institute of Allergy and Infectious Diseases (NIAID) inBethesda, Md., reported "Interfering with Apoptosis Ca2+-BindingProtein ALG-2 [apoptosis-linked genes] and Alzheimer's DiseaseGene ALG-3."

D'Adamio's Alzheimer's-associated ALG-3 apoptosis gene takes offfrom the discovery last summer by other investigators of a mutantgene on human chromosome 1 now known as STM2. (See BioWorldToday,) Aug. 18, 1995, p. 1.) The acronym STM stands for "seven-trans-membrane," which reflects the gene's encoded protein's sevenback-and-forth traverses of the cell membrane.

D'Adamio heads the T cell and molecular biology unit in NIAID'slaboratory of cellular and molecular immunology. What he came upwith was a gene fragment nearly identical to that SMT2 gene.

"We have cloned the full-length gene now from a mouse," he toldBioWorld Today, "and the homology with the human SMT2sequence is better than 98 percent."

Based on his mouse working model, D'Adamio suggests that "thisgene must be involved in Alzheimer's programmed cell deathpathway. And that in the familial Alzheimer's, where it is mutated,there must be a disfunction that may induce or trigger prematuredeath of neurons."

He added, "Our work is the first objective piece of evidence thatsome part of the programmed cell death pathway may play a role inAlzheimer's disease."

Within six to 12 months, he expects to go from his present in vitrofindings to in vivo confirmation in mice, as a possible prelude tofuture human trials and eventual applications. D'Adamio said, "Let'ssay that we have to show first that endogenous genes are involved incell death. Second, we have to show exactly what our truncatedtranscript makes. Third, we have to show in an animal model ofAlzheimer's disease that expression of this fragmentary proteinprotects against Alzheimer's."

Recalling that "lots of biotech companies are utilizing peptides astheir therapeutic agents," D'Adamio concluded: "If we can find apeptide that will block programmed cell death, specifically inAlzheimer's, and maybe in other diseases which are due touncontrolled induction of apoptosis, I think this would be of greatinterest to biotech companies."

Canadian Start-Up Starts Burning Research Money

A new biotechnology company, ApoptoGen, started up last month inOttawa, Ontario, to commercialize application of programmed celldeath to human disease. Alex MacKenzie and Robert Korneluk,principal co-authors of the paper in the current Nature launched thefledgling firm with $C1.7 million funding, put together by theCanadian Genetic Diseases Network, headquartered in Vancouver.

Manager Carol Smith, told BioWorld Today that the main investorwas the Canadian Medical Discovery Fund, "a group that does haveconnections to the government, and private industry as well." Othercontributors, she added, were the University of Ottawa and theChildren's Hospital of Eastern Ontario.

The Network's managing director, David Schindler, said that "thecompany has two patents pending, which cover seminal applicationsfor this new family of apoptosis genes."

ApoptoGen, Schindler said, has hired "some technicians and post-doctoral staff, and is already burning its financial reserves." Thecompany, he said, "intends to raise more money within a year."

Meanwhile, with Korneluk and MacKenzie as its main scientists,work is under way "on characterizing the genes and gene products." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.