From the Tucson Citizen, Aug. 10, 1998

Reprinted with permission from the Tucson Citizen, Monday, August 10, 1998

Tiny worm sperm big deal

UA research shows potential links to serious diseases.

By ANNE T. DENOGEAN
Citizen Staff Writer
When University of Arizona researcher Sam Ward tells people what he does for a living, they look at him as though he were a mad scientist in the flesh.

"It usually stops all conversation," he said.

But while Ward doesn't mind the strange looks and a few giggles about his research of worm sperm--yes, worm sperm--it's a serious endeavor, with implications for how medical science understands and treats human disease.

It already has increased the understanding of the genes involved with a certain human neuromuscular disease and an inherited form of Alzheimer's disease, said Ward, head of the UA department of molecular and cellular biology.

Worm is transparent

Caenorhabditis elegans (pronounced "see-no-rab-DITE-iss EH-leh-ganz") is a transparent worm less than 1/20th of an inch long, smaller than a ballpoint pen nib.

Researchers can grow thousands of them in the lab at a time.

Ward's lab is one of more than 500 around the world that study the Caenorhabditis' physiology, nervous system, embryos, muscles, proteins and cell development.

"We study the sperm because it's a fascinating cell. We like the biology of it. In practice, we can isolate the mutations that disrupt it," Ward said.

Ward noted that people "don't like thinking of

'If we can show that the same function is performed by a gene in worms and humans, we can figure out much more readily in worms what that function is.'

-Sam Ward,

University of Arizona researcher

(themselves) as being just large versions of little worms."

However, along with the fruit fly, the ordinary yeast cell and the mouse, Caenorhabditis elegans is considered one of the "model organisms" for the study of humans.

Nematodes have many of the same kinds of body tissues, such as nerves and muscles, that humans have.

Worms and humans are similar on a more basic level--a molecular level--Ward said.

The basic molecular machinery for building cells, causing them to move, causing them to associate to form other organisms, all evolved more than a couple of billion years ago, Ward said.

Having evolved from a common ancester, all creatures on Earth share the same cellular and biochemical strategies for living. The very genetic code that spells out the language of life is virtually identical in every life form from viruses to humans.

Therefore, these biological processes--including mutations in the processes--can be studied in many different organisms, including this worm. What is learned can then be related to humans.

Many of the genes found in nematodes, fruit flies and other model organisms have counterparts in humans that are so similar they are functionally interchangeable.

Adding to the knowledge

Ward's laboratory has turned up worm genes that are similar to human genes related to Alzheimer's disease and a specific human neuromuscular disease.

The information could be critically important to understanding what goes wrong in certain disease genes in humans.

"If we can show that the same function is performed by a gene in worms and humans, we

can figure out much more readily in worms what that function is--what is the biochemical process the gene is carrying out. "Then we can go back to humans and see if this is really doing the same thing in humans," Ward said.

Ward said the first gene for an inherited form of Alzheimer's disease was identified about three years ago from a study of families with the disease.

The scientist who identified the sequence of this gene searched through the databank of the National Center for Biotechnology Information in Bethesda, Md., the depository for all gene sequences.

"They found that the gene it matched the best with actually is a gene that we've identified from nematode sperm," Ward said. "That's the last thing one would have guessed.

Subsequently, another worm gene was identified in a laboratory at Columbia University that was even more similar to the Alzheimer's disease gene. Study of this worm gene has helped understand the function of the human gene.

In the nematode, it's a protein that plays a fundamental role in developing some of the membranes of the sperm.

In humans, "it's a membrane protein that's now known to play a role in inducing what is called amyloid plaques, which are deposits in the brain, which are common and are probably the cause or agent of the degeneration that leads to Alzheimer's disease," Ward said.

Ward also said he recently received a call from a clinical neurologist, who believes he has identified the gene related to a human neuromuscular disease. Ward can't name the disease at this time because the findings are not yet published.

The researcher found that the gene is similar to another gene Ward's lab has identified in the nematode sperm.

"They had no idea what the function of that gene was. We know something about it and we can study it much more easily. We are now collaborating to see how similar the genes are," Ward said.

The UA lab will experiment to see whether it can replace the worm gene with the human gene, something that has been done with the human Alzheimer's gene.

In the case of the Alzheimer's disease gene, the worm gene was knocked out and a tiny hypodermic needle was used to inject the DNA of the human gene, which could then replace the function of the worm gene.

"The human gene worked just fine in the worm," Ward said.

For a number of human diseases, Ward added, the mechanism has been worked out by going back and forth between the human form of the gene and the gene from yeast or worm.

That's particularly true of a large number of genes that mutate to form cancer.

"Since cancer involves cells dividing out of control these are genes that normally play a role in controlling cell division and it turns out that these same genes control cell division in yeast, in worms and humans."

If the impact of Ward's work is surprising to those who ask the innocent dinner party question--what do you do for a living?--it also is surprising to Ward.

Thirty years ago, Sydney Brenner, a researcher with the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, was the first to use the worm as a model for studying how genes control behavior and development.

Ward was one of Brenner's first postdoctoral fellows.

"If you had asked me when I first started working with worm sperm, would I find a gene for neuromuscular disease or Alzheimer's disease, I'd have said, 'Absolutely not.'"

To learn more about this research, you can check out the lab's Web site at http://www.mcb.arizona.edu/wardlab/.