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Stanford Report, November 14, 2001

Stanford scientists to probe inner workings of remarkable microbe


As concern mounts over the spread of anthrax and other types of germ warfare, it is worth bearing in mind that many microbes have the potential to benefit humanity. A Stanford research team has received a $2.5 million federal grant to study one such microorganism -- the bacterium Caulobacter crescentus, which scientists consider the premier model for understanding the mechanisms that regulate bacterial reproduction and growth.

Scientists have long been fascinated with the ability of Caulobacter bacteria to divide asymmetrically into two distinct daughter cells -- a "swarmer" equipped with a tiny tail for swimming, and a larger "stalk" cell shaped like a lollipop on a stick. This image shows a greatly enlarged Caulobacter cell in the process of dividing. Photo courtesy of: Caulobacter Microbial Cell Project

The Stanford team is one of 11 research groups recently funded by the Microbial Cell Project -- a nationwide initiative launched by the U.S. Department of Energy (DOE).

"Microbes have evolved for 3.8 billion years and have colonized almost every environment on Earth," DOE officials note on the project's website. "In the process, they have developed an astonishingly diverse collection of capabilities that will help DOE meet its challenges in toxic waste cleanup, energy production, global climate change and biotechnology."

The goal of the Microbial Cell Project is to create what DOE officials call "a comprehensive 'owner's manual'" for several species of bacteria, each endowed with a particular biological attribute. For example, the Stanford team will analyze C. crescentus -- a harmless, aquatic bacterium -- while military researchers will try to unlock the secrets of a different species that has the extraordinary ability to survive enormous doses of radiation.

Single-celled microbes "can work as miniature chemistry laboratories, making unique products and carrying out specialized functions," adds DOE. "The ultimate aim of this undertaking, and the rationale for DOE's concerted effort and focus, is to achieve the necessary level of understanding of cellular functions so that they can be manipulated intelligently."

Stanford project

The main objective of the three-year Stanford project, which began on Sept. 15, is to understand how all of the approximately 3,800 genes that make up the C. crescentus genome communicate with one another.

The life cycle of a Caulobacter swarmer cell is shown through a series of electron micrographs. To reproduce, the bacterium first loses its tail, then grows a stalk before dividing into new daughter cells --a swarmer and a stalked cell. The Energy Department has funded a team of Stanford scientists to determine the genetic mechanism that regulates the Caulobacter cell cycle. Photo courtesy of: Yves Brun/Indiana University

"About 40 percent of those genes are of unknown function," said Harley McAdams, a senior research scientist in the Stanford Department of Developmental Biology and principal investigator of the Stanford Microbial Cell Project.

"Trying to unravel the complete communication network of this bug is a very big and complicated problem," he said.

Last year, McAdams and Stanford colleagues received a Defense Department grant to study cellular regulation in C. crescentus and three other organisms.

"The two grants will complement one another," said McAdams, noting that DOE is interested in C. crescentus because of its potential as a bioremediation agent.

"Studies show that C. crescentus is capable of converting mercury, copper, cadmium, cobalt and other heavy metals into chemical forms that are less soluble and less toxic to people," said project member Alfred M. Spormann, associate professor of civil and environmental engineering at Stanford.

"DOE would like to find a bug that can go down and turn these toxic chemicals into something benign," McAdams noted, adding that colonies of C. crescentus often are found growing in noxious blooms in aquifers deep underground.

Conventional laboratories allow microbes to grow in non-stressful conditions, providing them with an abundance of food and an ideal living environment, he says.

"But in the wild, bacteria spend most of the time starving, because it's a tough life out there," McAdams said. "By exposing these organisms to a wide range of nutritional restrictions and environmental stimuli, including toxic chemicals, we will be able to pinpoint which genes turn on and off under different stresses. This will help define the purpose of some genes whose function is currently unknown."

Asymmetrical reproduction

Bacteria are single-celled organisms that reproduce by splitting in half -- creating two daughter cells of identical size and shape. Microbiologists have long been fascinated with the ability of C. crescentus, which divides asymmetrically into two different daughter cells -- a small "swarmer" cell equipped with a tiny tail that allows it to swim, and a larger "stalk" cell shaped like a lollipop on a stick. In fact, "caulo" is Latin for "stalk."

"Asymmetrical division is a fundamental biological process," McAdams said. "Without it, we'd turn out to be blobs without hair, teeth and other specialized cells. C. crescentus is one of the simplest organisms we can study to understand asymmetric cell division."

He points out that C. crescentus provides an ideal model system for studying bacterial reproduction, because it is easy to grow colonies of the bacteria that are all moving synchronously through their cell cycles.

Two co-investigators in the Stanford Microbial Cell Project -- Lucy Shapiro, the Virginia and D. K. Ludwig Professor in the Department of Developmental Biology, and Charles Yanofsky, the Morris Herzstein Professor of Biological Sciences, Emeritus -- have conducted pioneering research on the genes that control bacterial cell regulation.

Another co-investigator is Stanford alumnus Peter D. Karp, director of the Bioinformatics Research Group at SRI International Inc. in Menlo Park, Calif. Karp has developed powerful tools for browsing genomes and regulatory networks that will help translate genetic regulatory data gleaned from the project into a user-friendly format for the World Wide Web.

The Stanford team also will collaborate with DOE's Lawrence Livermore National Laboratory east of San Francisco, where researchers have received another DOE grant to create a cellular map detailing how proteins produced by C. crescentus interact with one another.

"To accomplish all of our goals requires a lot of people with different expertise," noted Michael Laub, a graduate student in developmental biology who will continue working on the Stanford project when he becomes a fellow at Harvard's Center for Genomic Research in January.

"The DOE grant is terrific because it gives us an opportunity to study the cellular biology of the microorganism in its natural environment," Spormann concluded. "It lets us see what the microbe is 'thinking.''