Confronting the big picture

According to Bob Horvitz, along with Sydney Brenner and John Sulston one of the winners of the 2002 Nobel Prize in Physiology and Medicine, there are four big-picture problems confronting biologists today.

These include hereditary mechanisms, of which Horvitz believes scientists are getting a pretty good understanding; developmental processes, where scientists know a few bits and pieces; the brain and nervous system, about which they know even less; and the process of evolution, which is still a black box.

Of these problems, Horvitz has spent the bulk of his career looking at the first two, and has had time to start looking at the third as well.

Horvitz started working in Brenner's lab in Cambridge in 1974, at the same time that Brenner was developing Caenorhabditis elegans as a model organism for the study of genetics and developmental processes.

Classical genetics

"I wasn't convinced about C. elegans at first... but I never looked back from when I started -- I saw what could be done with it," Horvitz says. At the beginning, the researchers were restricted to using classical genetics and biological approaches to the study of C. elegans, as the techniques required for the complex molecular manipulation of the organism had not been developed.

"At the point when I started with it there was no way to do any molecular biology on C. elegans, but I knew it would happen down the road," Horvitz says.

In Brenner's lab, Horvitz played a part in tracing out the complete cell lineage of C. elegans, a project spearheaded by John Sulston. Using microscopes to obtain a single cell level of resolution, Sulston and Horvitz painstakingly worked out the fate of every cell in the lineage -- from the single cell at fertilisation to the adult organism.

"The lineage lays out the developmental biology of the organism," explains Horvitz. With 959 cells in the adult, and 131 cells, which reproducibly perished during the process of development, Horvitz became interested in the mechanisms of cell death. Clearly there was a genetic component, with cells committing to a particular fate at each step of development.

In fact, Horvitz has demonstrated that there are four steps to achieving programmed cell death. First a cell makes a decision whether to live or die, a process that involves at least four genes. This triggers the process of suicide, via a cascade of genes that regulate the process.

The next step is engulfment, or phagocytosis, of the dying cell by a neighbouring cell, which appears to also play an active role in the dying cell's fate and involves a number of pathways. Finally, the dead cell is degraded in a process requiring another series of steps.

But the importance of programmed cell death in development has really been highlighted by the discovery of similar processes in higher organisms, which are being exploited by researchers in the hopes of discovering therapeutic methods to treat a variety of diseases, including cancer.

"The big breakthrough in terms of the novelty of the mechanism of cell death came when a cell death protein we cloned resembled a human protein. I got calls from five pharmaceutical companies the day we published the paper," Horvitz says.

The worm protein in question was CED-3, which was similar to the human protein interleukin-1 beta-converting enzyme (ICE), a protease implicated in inflammatory disease. Pharmaceutical companies were looking at ICE as a possible target for inflammatory disease. Subsequently, CED-4 was found to resemble Apaf-1, a human apoptosis protein, and CED-9 was similar to Bcl-2.

Horvitz's interest in C. elegans has not stopped with studies of cell lineages and programmed cell death; it extends into areas of signal transduction, neural development and behaviour, and more recently into the role of microRNAs in gene regulation.

He is a Howard Hughes Professor at Massachusetts Institute of Technology (MIT), and a founding member of MIT's McGovern Institute of Brain Research, where he is using C. elegans to study how genes control the development of the nervous system, and how the nervous system controls behaviour. He also works with researchers at Massachusetts General Hospital on human disease, including amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), using C. elegans to develop models.

And Horvitz has also been involved in the US biotechnology industry, starting up two companies to capitalise on his discoveries in the worm. IDUN Pharmaceuticals is targeting the control of programmed cell death to develop human therapeutics. An earlier company, Nemapharm, also used worm genomics to develop therapeutics, and was acquired by Sequana, which merged with Arris Pharmaceutical to become Axys Pharmaceuticals, and subsequently was bought by Celera.

The learning curve

Far from feeling stretched thin by the number of balls he juggles at any one time, Horvitz says he thrives on it.

"Each feeds into each other, it's very synergistic," he says. For example, he says the lab benefits from the knowledge of disease and drug discovery, and a degree in economics has given Horvitz a lifelong interest in business.

And along with the four big problems still facing biological researchers, there is still a lot to learn, he says. New technologies, including the use of RNA interference to systematically knock out genes, and proteomic approaches to elucidating components of complexes and interactions are incredibly powerful, Horvitz says.

"We're never going to be able to know the details about all things, but in principle, we should be able to make hypotheses and test them," he says.

"Now we have the tools to look at mechanisms, it's obvious that there is an enormous amount of conservation in biological mechanisms. We should be able to use models to define a framework and ask questions, then go on to more complicated organisms."

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