“I like to think that the fourth winner of the Nobel Prize this year is Caenorhabditis elegans and, of course, I think it deserves most of the honor although, of course, it will not share in the monetary rewards.” -- 2002 Nobel Prize Winner Sidney Brenner, MBBCH, Dr.Phil., president and director of Science, The Molecular Sciences Institute, La Jolla and Berkeley, California.
The three winners of the 2002 Nobel Prize in Medicine and Physiology were indeed human, but all acknowledged that they owed much to a worm so small that it is best seen under a microscope, so simple that one can trace the source of each of its 959 cells and so transparent that one can watch its life’s processes at work.
Meet Caenorhabditis elegans or as it is more commonly known – C. elegans.
It is actually a nematode—a smooth-skinned worm with a long, unsegmented round body that tapers at each end. It has only a few cells, but among those are a nervous system that even includes a “brain,” making it ideal for neuroscience. Because it has only a few cells, it is also a valuable tool in the study of development where the lineage of each of its cells can be determined.
Nobelist Sidney Brenner
Nobelist Brenner is credited with advocating the use of C. elegans because, as he wrote in a 1963 letter to Medical Research Council of Great Britain, “I have long felt that the future of molecular biology lies in the extension of research to other fields of biology, notably development and the nervous system.”
Simplicity of anatomy, genetics and maintenance in the laboratory are the hallmarks of C. elegans, said Henry Epstein, MD, professor of neurology at Baylor College of Medicine.
Henry Epstein, M.D.
“We grow the worms in Petri dishes, similar to the ones used for bacteria,” he said. “In fact, we grow them on bacteria. They are descended from soil nematodes that eat bacteria in and around the roots of plants.”
“The initial reasons for using it were simplicity of anatomy and the ease of maintaining it in the laboratory,” said Epstein. “Its anatomy is so simple that you can follow by microscopy the entire development of the organism on a cell-by-cell basis.
“When I started working with it, there were no more than half a dozen laboratories working with it,” he said. The numbers have grown exponentially around the world, he said.
Sequencing the worm genome
When scientists began toying with the notion of determining the genetic sequence of entire organisms, C. elegans was first and “served as a basis for the human, mouse and other genomes,” said Epstein. Approximately half the genes in C. elegans are closely related to genes in humans and mice.
In his laboratory, Epstein is particularly interested in a particular protein called a chaperone that is necessary for the proper folding of the portions of myosin molecules that are critical in the development of muscles as well as in their function. The research has implications for certain forms of heart diseases and for heart failure. Because it may also have an effect on cell division, it also provides a target for chemotherapy against cancer.
The phylum or general class of animals to which C. elegans belongs has existed for 600 million years, said Epstein. “Some are as divergent from one another as sharks and humans. It is a broad phylum of organisms that fill many different environmental niches. Many are parasitic. Many live in the sea. Others live in soil, still others in plants.
Mutant worms
Under a microscope, one can easily separate the mutant worms from the normal ones. From there however, said Tae-Ho Shin, Ph.D., assistant professor of molecular and cell biology at Baylor, one can go directly to the cellular process that has gone awry and discover where the mutation lies. C. elegans is an excellent tool for studying aging as well as early development and neurology, he said.
Tae-Ho Shin, Ph.D.
His work concentrates on germ cells—those that carry out the task of reproduction. They are the precursors of gametes and make oocytes and sperm.
“When an embryo is first made, it has the capacity to make an entire organism,” said Shin. “As the cell divides, the ability to make that entire organism in subsequent cells is lost.”
“The potential totipotency is somehow retained in the germ cells,” he said. He is trying to figure out what totipotency actually means, and “C. elegans seems a good system for that.”
Currently, his laboratory is working with a protein – pie-1 – that is somehow critical to totipotency. When it is mutated, the germ cells start the process that would result in making different tissues, but they are blocked.
Another function of pie-1 seems to be in the packaging of DNA for non-germ cells called somatic cells.
Dying cells
Zheng Zhou, Ph.D.
Zheng Zhou, Ph.D., assistant professor of biochemistry at Baylor, studies how the remains of dying cells are cleared from the body. The cells die because of a process called apoptosis or programmed cell death. In a way, cells “suicide” because that is best for the organism.
“For this particular question – how cells die and are cleaned away – C. elegans is a good simple system,” said Zhou. “It is genetically tractable, and you can make any mutations you want. You can see every cell under the microscope.”
In fact, she can actually watch a cell die under the microscope. “That’s an advantage that no other organism can match,” she said.
“Basic biological process happens in similar ways in worms compared to humans,” she said. “We can use it with confidence. What we know in worms, we can use for similar processes in humans.”
Anna M. Newman, Ph.D., an assistant professor in biochemistry at Baylor, studies the development of the uterus and vulva in C. elegans and how the two different kinds of tissues join together. She too finds the worm a valuable tool in her work.
Work with C. elegans spans less than 40 years, but as a tool, it has opened doors in many fields. As Urban Lendahl, Ph.D., an associate member of The Nobel Committee for Physiology and Medicine said at the presentation of the awards to the winners of the 2002 Prize:
Anna M. Newman, Ph.D.
“This year's Nobel Prize celebrates the Joy of Worms. Brenner's almost prophetic visions from the early 1960s of the advantages of this model organism have been fulfilled. It has given us new insights into the development of organs and tissues and why specific cells are destined to die. This knowledge has proven valuable, for instance, in understanding how certain viruses and bacteria attack our cells, and how cells die in heart attack and stroke. Sydney Brenner, Robert Horvitz and John Sulston. Your discoveries concerning the genetic regulation of organ development and programmed cell death have truly opened new avenues for biological and medical research. On behalf of the Nobel Assembly at Karolinska Institutet I wish to convey to you our warmest congratulations and I ask you to step forward to receive the Nobel Prize from the hands of His Majesty the King.”
(Editor’s Note: This is the second in an occasional series of articles spotlighting the organisms important in a variety of biological studies. Drosophila melanogaster, the fruit fly, was first to be featured).