By David N. Leff

In the world of roundworms (Caenorhabditis elegans), the title, ¿long-term observer of death,¿ belongs to geneticist and developmental biologist H. Robert Horvitz, at the Massachusetts Institute of Technology.

In the past 15 years, he has discovered in this tiny, transparent nematode many of the genes controlling programmed cell death ¿ apoptosis. Homologous genes exist in Homo sapiens, and many nematode-runners believe that the dot-size beastie¿s cell-suicide process, which involves other cells that engulf the death-row cells, may also take place in humans.

¿In people,¿ Horvitz explained, ¿there are specialized engulfing cells called phagocytes ¿ in particular macrophages. In C. elegans it turns out that there are not such dedicated cells, but many things in that worm are very efficiently done. So what happens,¿ he continued, ¿is that in C. elegans various cells undergoing apoptosis are engulfed by neighboring cells. These have the property of being able to recognize, surround and eventually swallow a dying cell.¿

Human embryos take nine months to be born, and 15 or 20 years to grow up sexually. Roundworms mature in 3.5 days ¿ ¿from egg to egg,¿ Horvitz observed. ¿The adult worm,¿ he added, ¿has 947 main body cells, of which 131 will undergo apoptosis.¿ The first multicellular animal to have its entire genome sequenced, in 1998, C. elegans weighed in at some 19,000 genes, most of which encode proteins.

It¿s during that development phase that the worm¿s seven phagocytosis genes kick in. Horvitz explained why so many of these 131 naove cells become redundant and are discarded:

¿The interesting question is, Why make cells that are going to die?¿ The answer depends upon the cell,¿ he said. ¿Essentially, what we¿re seeing are the consequences of evolution. The way genes evolve is that they duplicate, and then one copy is free to go off and meander, by random mutation and selection. It looks as if cell lineage evolved in much the same manner. So what we see is the expression of equivalent sublineages where not all the cells that are generated are needed in all the different places of the animal. So basically the roundworm selects cells here and there, and the ones it doesn¿t need it kills off.¿

Engulfment¿s Double-Duty Gig

Horvitz, who holds an endowed chair of biology at MIT and the Howard Hughes Medical Institute, is senior author of an article in today¿s issue of Nature, dated July 12, 2001. Its title: ¿Phagocytosis promotes programmed cell death in C. elegans.¿

¿The basic finding of the study,¿ Horvitz told BioWorld Today, ¿is that this process of engulfment is not only a cleanup operation by janitor cells, which remove the cell corpses from the body, but also facilitates the apoptotic killing itself. If the engulfment process is perturbed, the cell-killing process is less robust. That¿s our basic finding.

¿What it says,¿ he went on, ¿is that in this biologically and medically important process of apoptosis, something really fundamental has been missed. It¿s either somebody or something is alive or dead. But in any dying circumstance, of an individual or a cell, there may be a state in between where someone can be very sick, but undead.

¿Our Nature report,¿ Horvitz went on, ¿says that cells initiate the death process. They look very much as if they¿re dying, but if engulfment doesn¿t occur, then at some frequency the cells make a comeback and recover. Without engulfment, apoptosis does not necessarily go to completion of the death process.¿

He illustrated his ongoing research with this human drama:

¿Say you come across a dead body. Your first question: Was it suicide or murder? However, there can be an intermediate circumstance. If I pointed a gun at your head and said, Kill yourself,¿ and then you killed yourself, the mechanism by which you died would be suicide. But I would have had a causal role.

¿What we think is going on in the roundworm,¿ Horvitz recounted, ¿is that the phagocytic cells are causing the suicide process of the dying cells, signaling, Go on, really kill yourself!¿

¿The questions we¿re pursuing now are: What¿s the signal? How is it read and responded to? And how does it integrate with the death process? How does apoptosis work overall? That means engulfment has a role in promoting the completion? What controls it, on a cell-by-cell basis? What decides whether a given cell will live or die? And finally, how does the death occur? We don¿t know.¿

From Roundworm Cell Death To Drug Design

¿Then you ask me,¿ Horvitz said, ¿where do I hope this ongoing research goes? I hope it goes into the clinic. We want to understand the basic biology, and how to apply it, because when the biology of apoptosis goes wrong, you get disease.¿

Emphasizing the conjectural nature of his therapeutic concepts, Horvitz suggested: ¿In traumatic brain injury and stroke, in neurodegenerative diseases, also in myocardial infarction, you have regions of cells that are dying. That means at the perimeter of those spreading regions cells are poised on the edge between life and death. If phagocytes are involved, then you¿ve got an opportunity. The concept would be: prevent the phagocytosis, and rescue cells that might otherwise die. Cells that are ready to go, but have to be pushed over that little bit to death. A simple strategy,¿ he observed, ¿would be to block the receptor that¿s on the phagocyte that can¿t recognize the dying corpse. We¿ve identified that receptor in C. elegans; we know what it is.

¿With disorders like cancer,¿ he continued, ¿what we would like to do is facilitate the recognition of tumor cells by murderous phagocytes. This is a conceivable alternative, but a bit more complicated for drug discovery. Because what you would do is try to push the tumor cells into apoptosis. This of course, is a major therapeutic goal in many pharmaceutical companies today. We offer another way to think about doing it.¿

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