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August 12, 2004
Clams: They're Not just for Chowder Anymore
International Team of Scientists Hopes to Pry Open Part of the Clam Genome
Woods Hole, MA—New England’s favorite summertime delicacy, the chowder clam, has just been elevated to a whole new status. An international team of scientists—who credit studying surf clam (Spisula solidissima) cells with important research breakthroughs in the study of diseases such as cancer, premature aging, and muscular dystrophy—has just convened at the Marine Biological Laboratory to begin sequencing some of the clam’s active genes.
The effort, called the Clam Project, is the first step toward sequencing the entire clam genome, and its goal is to provide scientists with better knowledge of the clam’s active DNA. Such information is crucial to the study of the basic cellular processes involved in many diseases. The scientists plan to use the new genetic information to create antibodies. And they hope to begin experiments impossible without those antibodies as soon as the project is complete.
The research team includes: Avram Hershko of Technion-Israel Institute of Technology, Yosef Gruenbaum of Hebrew University of Jerusalem, Robert Palazzo of Rensselaer Polytechnic Institute, and Robert Goldman of Northwestern University.
“Sequencing the clam genome would be a quantum leap for our research,” says Hershko, whose study of clams may someday lead to a better understanding of the causes of cancer.
The four clam researchers all focus on mechanisms that regulate the cell cycle. The Goldman Lab focuses on the structural proteins that are responsible for organizing the structure of the cell’s nucleus. When these proteins are genetically altered in meiosis, human diseases often result. In one such disease, progeria, children age unusually quickly. Goldman says that as rare as that disease is, the NIH has become interested because children with the disease display nearly all the symptoms of aging that the non-diseased elderly do. Understanding the aging process is becoming more and more critical as the elderly become an increasing portion of the American population.
Other diseases related to these nuclear structures include muscular dystrophy, lipodystrophy, cardiomyopathy, neuropathology, and mandibuloacral dysplasia. “I am sure we are just now hitting the tip of the iceberg with the number of diseases our research will shed light upon,” says Goldman.
All the researchers agree that the MBL’s proximity to the waters where the clams are collected, and the ability to interact in person with fellow researchers, are the keys to success for this project. “Every technique, every idea, you have people to consult with,” says Gruenbaum. “You can exchange ideas, even get new ideas about how to proceed while eating clam chowder.”
FACTS ABOUT THE CLAM PROJECT:
BACKGROUND
Biomedical researchers the world over credit the study of marine organisms with major breakthroughs in topics as varied as vision, the functioning of nerves, and the cycle of cell division. Yet a lack of genetic information for some of the marine organisms most commonly used in biomedical research, such as the surf clam (Spisula solidissima), has all but halted efforts to explore some basic cellular mechanisms.
GOAL/METHODS
The goal of the Clam Project is to sequence all RNA produced at any time in the clam’s life. Hershko’s team will sample RNA from fertilized clam eggs at different stages of development. Eventually, the group plans to have matched all that RNA to the DNA that codes for it. Hershko expects the total number of active clam genes to come in at between 12,000 to 20,000 genes, though he says the actual number is impossible to predict. Researchers do not yet know the total number of genes in the entire clam genome.
The sequencing of some of the clam’s active genes represents the creation of a powerful tool for yet further research. After posting the sequence to a public website, each of the four collaborators plans to use the new information for his own experiments. Because so many basic cellular mechanisms have been conserved by evolutionary processes, researchers expect the Clam Project to improve their understanding of processes in other species whose genes have already been sequenced, including humans. “This is going to help us make the clam more important as a cell biological, developmental, biochemical, and even molecular research tool,” says Goldman.
FUNDING
This research is made possible through the generous support of the Manhattan-based Gruss Lipper Family Foundation.
ABOUT THE RESEARCHERS
Avram Hershko continues to study the role of a protein called ubiquitin (which he discovered during previous work with clams) in the intricate ballet of molecular movement that makes up mitosis, one form of cell division. When cells divide correctly, they make perfect copies of their DNA. Usually, those DNA copies only split apart after each copy has been attached to a ‘thread’ within the cell. The threads pull the DNA copies into the nuclei of the newly forming cells. By duplicating and then evenly dividing DNA while cells reproduce, cells conserve genetic information critical to cell life and further division. Hershko hopes that the RNA sequencing will reveal new molecules in the biochemical pathways that usually allow the DNA copies to separate only after the threads are in place. Only a biochemical model constructed outside the cell, says Hershko, will allow him to determine the sequence of events in which different molecules regulate this process, and to learn why it sometimes goes wrong. As some experts believe that this incorrect division is important in the progression of cancer, Hershko’s work may move the world a step closer to understanding one fundamental part of the origin of cancer.
Yosef Gruenbaum’s research focuses on nuclear membranes and their role in nuclear envelope breakdown (NEBD) during meiosis, the form of cell division particular to the production of eggs and sperm. “It’s not clear what is going on. There are different models for NEBD, and the models do not all agree with each other,” says Gruenbaum. The clam, because the development of its eggs naturally pauses just before NEBD, is a great model to study the process. Researchers can fertilize eggs or stimulate them with salts, triggering instant breakdown of the nuclei as it releases its contents to form the nuclei of new cells. The ability to synchronize this stage of development in many different clam eggs makes it relatively easy to gather enough raw material to study particular stages of cell division.
Robert Goldman’s experiments focus on the nuclear lamina, which is made up of proteins known as lamins. The lamina lies just inside the nuclear envelope. Goldman values the clams for the ease of gathering enough nuclear lamins to use for biochemical studies. Although responsible for many activities ranging from DNA replication and transcription to determining the size and shape of the nucleus, the lamins represent a relatively small quantity of the molecules that make up the cell. The nucleus, however, is enriched in lamins, which help to give nuclei shape. “If you take a batch of eggs, within minutes you can have a small test tube full of isolated nuclei,” says Goldman, “and the nuclei retain their cellular architecture beautifully.” Goldman also values the clam nuclei for apparently containing only one kind of lamin, instead of the several found in the nuclei of frog eggs or human eggs. This means that it is easier to produce antibodies to determine which proteins are involved in the assembly and disassembly of the lamina during cell division. Antibodies are critical for biochemical investigations.
Robert Palazzo is trying to understand what goes wrong when cells create too many centrosomes, subcellular structures responsible for physically organizing the cell before and after cell division. When incorrect numbers of centrosomes are produced and get involved in managing cell division, chromosomes can end up where they are not supposed to be. Many tumor cells, for example, have an abnormal number of centrosomes. Palazzo’s work may lead to a way to correct errant centrosome function in tumors, denying cancers the ability to grow further.
ABOUT THE MBL
The Marine Biological Laboratory is an international, independent, nonprofit institution dedicated to improving the human condition through creative research and education in the biological, biomedical and environmental sciences. Founded in 1888, the MBL is the oldest private marine laboratory in the Western Hemisphere. Each summer, more than 1,400 scientists and students from around the world convene here to conduct research and collaborate.
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