It is possible that in the future, people will be able to snuggle up to their cell phones, live under power-lines and light up a cigarette with less fear of their own mutinous cells reeking bio-havoc.
Researchers from the Rothman Lab at UCSB’s Neuroscience Research Institute have located gene p53 in a species of nematode worm known as C. elegans. More advanced versions of the same gene are already known to exist in the human body, and when absent or mutated, they cause over 50 percent of all cancers. The team of researchers was led by molecular, cellular and developmental biology professor Joel Rothman, and included post-doctoral fellow Brent Derry and graduate student Aaron Putzke.
The findings, already available online, will be on the racks in Science magazine on Oct. 19 and promise to make headway in the search for a cure for cancer, Rothman said. The simple, fully sequenced genome of C. elegans provides a good model for many types of research, as opposed to humans and mice, which are costly and complicated.
“It’s a great experimental model, but if you want to understand human disease, you think, ‘what good is it to study this lowly worm?'” Rothman said. “What we’ve come to realize in the last decade or so is that many of the genes and many of the processes that go wrong in human disease are present in these worms and do the same kinds of things. So if you understand a basic fundamental mechanism that can go wrong in another animal, you can get a long way toward understanding it in humans.”
Rothman, Derry and Putzke asked whether the p53 gene, originally found in humans, was also present in C. elegans. Despite reports in such high-profile journals as Science magazine saying that it was not, Derry found it was.
“Many people have exhaustively searched the completely sequenced C. elegans genome, which is available free to the world, and failed to find the p53 gene. Therefore, it was thought to be absent from this organism,” Derry said.
Derry decided to take a second look.
“When I joined Dr. Rothman’s lab I decided to look for the gene [in C. elegans] myself,” he said. “And lo and behold, was able to find it using several computer-based approaches. It’s cryptic; it’s difficult to say for sure through the sequence comparison. … Joel and I would have these discussions; he always said, ‘Yeah! I think it’s p53.'”
The p53 gene is the most important gene in human cancer, Rothman said. It is the only gene that has ever been on the cover of Newsweek magazine. By initiating programmed cell death it protects the body from cancers.
Rothman’s lab studies programmed cell death, also known as apoptosis – a normal process that all animals carry out to rid themselves of cells they do not want.
“In shaping an embryo into a human, there’s lots of programmed cell death that occurs,” Rothman said. “It’s a way of sculpting out a shape, like a sculptor chipping away at a piece of stone and underneath it creating a beautiful sculpture.”
The discoveries of genes in C. elegans that control programmed cell death have, in less than a decade, led to many new drugs that are currently being tested to treat neurodegenerative disease in humans.
“There is a whole slew of diseases that result from defects in programmed cell death,” Rothman said. “In medicine, programmed cell death is very important. It is the first line of defense against cancer. Cells have a way of knowing if they are becoming cancerous.”
“[The gene p53] is the mediator, or gatekeeper, of the genome, because it can recognize damage of the genetic material, DNA, and do something to respond to that damage. We call that damage genotoxic stress – it’s what carcinogens and radiation cause,” Rothman said.
Most cancers can be traced back to some defect in the p53 process. Thus, p53 is an obvious target for intervention for those who wish to develop an anti-cancer drug that will be more effective against cancer cells and less harmful to the rest of the body, Derry said.
“The problem with cancer therapies now is they are devastating to the patient.” Rothman said. “You’re taking nearly lethal doses of compounds that act in a very non-specific way. It’ll be possible in the next decade or so for pharmaceutical companies to develop drugs that are very specific to the cancer cell only, and completely innocuous for the rest of the organism.”
Finding the necessary compound and designing an anti-cancer drug that will have the desired effect is like “looking for a needle in a haystack,” Derry said. The discovery of p53 in C. elegans expands the horizons of cancer research, but it is highly unlikely that the new information will produce an immediate cure.
“In science you don’t want to give too much false hope. We had to work extraordinarily hard in order to get this paper in Science. It was great when we heard it was accepted,” Derry said.
Another possible roadblock is the fact that nematode worms and humans are very different genetically. Humans have three p53-like genes and nematodes only have one very primordial one.
“There are specific regions of [the gene] that are highly conserved and very similar to the human protein,” Putzke said. “There may be functions in the worm that don’t exist in the human, and there may be functions in the human that don’t exist in the worm. So the key is to find what’s the same in both systems – in this case, apoptosis.”
The scientists’ work has prompted a Bay Area biotech company to pursue cancer drug targets based on the worm’s p53 gene. Rothman, Derry and Putzke said the research is also likely to attract more graduate students to the Rothman Lab, the MCDB department and the Neuroscience Research Institute, and also attract more funding from outside sources.
“I received funding from the Cancer Center of Santa Barbara as well as the Tri-Counties Blood Bank — local money from grass roots organizations,” Derry said. “That’s very cool. It’s local money and in a way we’ve made a splash with the research. They deserve some praise because it may not have been possible to do without their money.”