Studying Cells and the Molecules Within Them
Research supported by the Division of Cell Biology and Biophysics illuminates the structure and function of cells, cellular components, and the biological molecules — proteins, lipids (fats), and genetic material (DNA and RNA) — that make up these components. The long-term goal of the Division is to find ways to prevent, treat, and cure diseases caused by abnormal cellular activity.

Exploring the Birthplace of Proteins
One way to examine the role of various molecules in health and disease is to decipher and study details of the molecules' three-dimensional structures. For scientists who study such structures, one of the most thrilling moments in recent history came in 1999 when, capping more than 30 years of effort, three groups of NIGMS-supported researchers unveiled the structure of the ribosome — the cellular birthplace of proteins in every living creature.

The first structural snapshot of an entire bacterial ribosome. Detailed studies of this structure will help researchers better understand how proteins are made. They may also lead to new or better antibiotic medicines. Ribosome structure courtesy of Jamie Cate, Marat Yusupov, Gulnara Yusupova, Thomas Earnest, and Harry Noller. Graphic courtesy of Albion Baucom, University of California, Santa Cruz.

To most people, ribosomes are tiny. Tens of thousands would fit on the sharpened tip of a pencil. But to scientists, ribosomes are huge. Each is a molecular machine with many moving parts, including several strands of the genetic material RNA and more than 50 small proteins. The ribosome is by far the largest molecular complex yet to shed its structural secrets. These secrets include how its many pieces fit together and exactly where proteins are made.

As a spin-off benefit, the work may advance the design of antibiotic drugs. Many of today's antibiotics work by sabotaging bacterial ribosomes. By comparing the overall structure and internal channels and caverns of bacterial ribosomes with those of higher organisms such as humans, researchers may be able to design compounds that clog the works of bacterial ribosomes but leave human ribosomes alone. This could lead to new antibiotics that are highly effective and have minimal side effects.

Cell Movement Studies Track Herpes to its Hideout
Many NIGMS-supported scientists focus on individual cells — the fundamental units of life. By studying what happens inside, on, or around cells, researchers can reveal life's most basic and essential activities — how cells move, divide, or communicate with each other.

Bearer's team injected herpes virus particles into giant squid nerve cells to study how viruses travel inside cells. The virus appears green because it is labeled with a fluorescent protein. The round bead in the middle of the cell is an oil droplet that marks the injection site. Photo: Elaine Bearer

Take, for instance, the work of Elaine Bearer of Brown University and her colleagues. Their studies of how cells transport internal cargo revealed long-sought secrets about the herpes virus.

Herpes is a major cause of infectious corneal blindness as well as a host of other diseases ranging from cold sores to life-threatening brain inflammation. The disease is especially dangerous for infants and those with weakened immune systems.

Scientists already knew that even when a herpes infection seems to have receded, the virus hides out in nerve cell bodies, emerging periodically to cause new flare-ups. But until Bearer's group made it clear, researchers didn't know exactly how the virus travels from the nerve ending to the cell body.

The scientists track the virus as it travels in giant squid nerve cells. These cells are research favorites because they are enormous, making them easy to work with. Each cell is about 7 centimeters (2.75 inches) long and almost a millimeter wide — about the size of a small, straightened-out paper clip.

Bearer and her coworkers discovered that the virus moves in one direction, and it travels at the same constant speed as specialized cellular structures called organelles. The researchers concluded that the virus takes over the nerve cells' own internal transport machinery.

Other studies confirmed this, strongly suggesting that the herpes virus plays the same trick in humans. Understanding how the virus travels within nerve cells may lead to new treatments for herpes infections. It also teaches us more about cellular transport, a process that is essential to life.

Protein Fragments May Undergird New Cystic Fibrosis Drug
Cystic fibrosis (CF) is one of the most common fatal genetic diseases in the United States. Approximately 30,000 Americans have CF and an estimated 8 million are carriers of it.

John Tomich of Kansas State University and his colleagues designed protein fragments that may be the basis of a new drug to treat CF. These fragments, called peptides, may substitute for a protein that often malfunctions in those with the disease. This protein is called cystic fibrosis transmembrane conductance regulator, or CFTR.

CFTR is an "ion channel protein" that controls the flow of chloride ions (a component of salt) into and out of cells. When CFTR does not work properly, the balance of salt inside cells is out of whack, leading to a buildup of abnormally thick mucus that clogs the lungs, intestines, and pancreas. Those with CF have trouble breathing and digesting food, and they frequently suffer from persistent lung infections.

Tomich's team discovered that bits of a brain protein similar in salt selectivity to CFTR can substitute for the defective CFTR proteins. These brain peptides form chloride channels that restore the salt balance in mice that have a genetic defect similar to the one in most people with CF.

If researchers can develop a peptide that forms chloride channels in those with cystic fibrosis, there's a chance it could help treat the disease. Toward that end, Tomich's group continues tweaking the brain peptides to improve their potential as drugs, such as their ability to be delivered and absorbed by cells. The scientists have already examined more than 100 variations of the peptides. Tomich is also interested in using the same strategy to treat other disorders, including stroke and epilepsy.

Studies of Dividing Cells Uncloak Cancer Cause
One of the most dramatic activities that cells accomplish is cell division, in which a cell must copy and sort out evenly all of its genetic material (chromosomes), then pinch itself in two. The complex dance performed by chromosomes just before cell division fascinates Conly Rieder, a cell biologist at The Wadsworth Center in Albany, New York. His team's work revealed how asbestos, previously used in ceiling tiles and insulation, can cause a wide variety of diseases, including lung cancer. By studying dividing newt lung cells, Rieder and his coworkers discovered that spear-like asbestos fibers can needle their way into the nucleus of a cell, where they may snag, sever, or stab chromosomes. In rare cases, the fibers may disturb chromosome sorting during cell division, which can lead to cancer and other disorders. Once asbestos fibers are lodged inside cells, they are passed on to each succeeding generation of cells, continually increasing the risk of serious genetic damage.

For several decades, NIGMS has supported scientists who determine the detailed structures of proteins and other molecules. These structural biology studies have shed brilliant light on specific proteins.

But now, NIGMS has launched an additional, more organized effort in a related field called structural genomics. As its name implies, structural genomics hinges on the relationship between protein structures and gene sequences. (A genome is an organism's complete genetic sequence.) The driving force behind this effort is the desire to forge a "shortcut" to solving protein structures.

The NIGMS structural genomics project, formally called the Protein Structure Initiative, is designed to group proteins into structural families based on their gene sequences. The participating scientists plan to solve the structures of representative proteins from each family. These structures will provide valuable information about the relationship between gene sequences and protein structures. With this knowledge as a guide, scientists will use computer modeling to predict the structures of all other proteins, saving them the time-consuming work of solving these structures by traditional means.

For more information about the structural genomics initiative, see http://www.nigms.nih.gov/Initiatives/PSI/.