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In this section:
» Understanding Life Processes at the Molecular Level
» Basic Studies Illuminate Disease Mechanisms
» New Approaches to Therapeutics
» Promising Technologies
These science advances convey the breadth and significance of NIGMS-supported research. Although only the lead scientists are named, coworkers and collaborators contributed substantially to the achievements.
Understanding Life Processes at the Molecular Level
Gene Silencing Illuminates Innate Immunity
Our world is teeming with potential health threats in the form of bacteria and viruses. Standing guard is the body's first line of immune defense, the innate immunity system. Despite the system's importance, researchers know relatively little about how innate immunity works. However, they have recently learned that the core molecular elements of innate immunity appear remarkably alike in organisms as diverse as plants, insects, and people. Thus, researchers are poised to answer key questions about this process by doing experiments in simple organisms.
In a recent example of the benefit of such an approach, Patrick O'Farrell, Ph.D., of the University of California, San Francisco, used laboratory fruit flies to search for fundamental clues about innate immunity. Harnessing the power of the revolutionary gene silencing technique called RNA interference (RNAi), which was featured in last year's story of discovery, O'Farrell used robotic methods to rapidly and systematically inactivate each of more than 7,000 fruit fly genes that are close counterparts of genes in humans and animals. He then identified those genes whose loss had a recognizable impact on the insects' ability to fight off germs. The strategy paid off, and O'Farrell discovered two fruit fly genes that are involved in carrying out the basic functions of innate immunity.
Since the fruit fly genes bear close resemblance to human genes, this work should quickly yield insights about how the proteins encoded by these genes function in human innate immunity. O'Farrell's findings are significant in another important way, as well. The results lend support for using RNAi to investigate complex molecular networks, which are known to be central to the function of both healthy and diseased cells.
Clarifying How Cells Connect
Connections between cells are critical for everything from embryonic development to holding the nervous system together. One of the ways that cells keep in contact is through fingerlike projections called neural cell adhesion molecules (NCAMs) that attach to the same molecules on neighboring cells. Exactly how these molecules bind to each other has been the subject of intense study, resulting in two, seemingly contradictory models. One model postulates that the NCAMs overlap just at their ends, as if the cells are touching each other by their fingertips. The other model supposes that the NCAMs overlap much more extensively, as if the cells are holding each others' hands palm to palm.
New research by Deborah Leckband, Ph.D., of the University of Illinois at Urbana-Champaign shows that both models are correct. Leckband measured the strength of the attachments between cell membranes at various microscopic distances and found that strong attachments occur at two clearly defined lengths, each corresponding to one of the competing models.
In addition to reconciling earlier research findings, Leckband's results offer fresh hints about how NCAMs work. The different bonding arrangements may reflect a two-step process by which cells adhere—as if first touching their fingertips before forming a tighter clasp. Alternatively, having two bonding configurations could allow cells to adjust their proximity to serve different needs. Studying how cells connect to each other not only sheds light on a critical life process, it will also help scientists better understand—and someday perhaps prevent—birth defects and certain cancers.
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Basic Studies Illuminate Disease Mechanisms
New Inhibitors Block Anthrax Toxin
In the fall of 2001, anthrax-contaminated letters sent through the mail caused 11 cases of inhalation anthrax, 5 of which were fatal. This bioterrorist attack focused national attention on the need for new ways to treat the previously uncommon infection, which is caused by the bacterium Bacillus anthracis. Unless antibiotics are administered quickly, they typically fail in treating inhalation anthrax because destroying the bacterium does not neutralize the effects of its three different toxins. One toxin, protective antigen, forms a tunnel through host cell membranes by which the other toxins, edema factor and lethal factor, enter and kill cells. Scientists have found that blocking the passage of lethal factor into cells reduces the severity of anthrax in animals, suggesting that this toxin is a good target for drugs against the disease.
Taking a different approach to foiling lethal factor, Lewis Cantley, Ph.D., of Harvard Medical School has devised a way to prevent the toxin from attacking cellular proteins. Cantley analyzed millions of small proteins to identify chemical inhibitors that latch onto and block the part of lethal factor that would otherwise attach to its targets.
The method worked. Cells in laboratory dishes that were treated with one of the inhibitors survived exposure to lethal factor, while untreated cells died. Cantley then determined the three-dimensional structures of lethal factor attached to several of the inhibitors, which enabled him to observe precisely how the inhibitors bind to the toxin. This information may now be used to design new drugs to combat anthrax.
Human Lung Cells Can Break Up Bacterial Gangs
While bacteria cannot speak or hear, their livelihood and ability to cause infections rest on effective communication skills. Large assemblies of networked bacteria called biofilms communicate by quickly trading chemical messages back and forth through a process known as quorum sensing. Scientists know that certain harmful bacteria use quorum sensing to evade the human immune system, and they also understand a good deal about how biofilms form and function. Until now, though, researchers were not aware that the human body could defend itself against quorum-sensing bacterial behaviors.
E. Peter Greenberg, Ph.D., of the University of Iowa in Iowa City discovered that one type of human lung cell, called an epithelial cell, has the means to cope with the potentially harmful quorum sensing that occurs within certain biofilms. He grew epithelial and other types of mammalian cells in laboratory dishes, then added molecules used in quorum sensing by Pseudomonas aeruginosa, the bacterium that causes most of the fatal lung infections in people with cystic fibrosis. Greenberg found that only the epithelial cells were capable of short-circuiting quorum sensing through the actions of an enzyme that blocked the bacterial signal.
The work is noteworthy because it suggests the existence of a built-in human defense system against certain serious bacterial infections, including those common in people with cystic fibrosis. Scientists could capitalize on this new knowledge in searching for medicines to boost the body's natural ability to stop quorum-sensing signals. The research may also point to other innovative approaches to treating chronic infections linked to biofilm formation.
Cell Growth Protein Predicts Return of Prostate Cancer
Two men of the same age have been diagnosed with an advanced stage of prostate cancer. Both individuals follow their doctors' advice and undergo surgery to remove the malignant walnut-sized gland, which is involved in male reproduction. Although the patients are similar clinically, they may face different futures because the tests used to detect the cancer are poor predictors of whether the disease will return after removal. However, a close look at a protein present in many types of cancer cells reveals a new tool for forecasting a man's risk of prostate cancer recurrence.
Kun Ping Lu, M.D., Ph.D., of Beth Israel Deaconess Medical Center in Boston, Massachusetts, has spent years studying the protein Pin1, which helps regulate the growth and division of cells. He had previously shown that some types of cancerous tissue contain increased levels of Pin1.
Lu wondered if the Pin 1 levels he found in prostate cancer cells might signal the recurrence of the disease following surgery. To test this idea, he measured the amount of Pin1 contained in the malignant tissue removed by a single surgeon from hundreds of men diagnosed with prostate cancer. Lu then followed up with 580 of the men to find out if they were still cancer-free. This work revealed a link between levels of Pin1 at the time of surgery and prostate cancer recurrence. In fact, the higher the level of Pin1, the more likely it was that the disease would come back.
This finding suggests that doctors could measure Pin1 levels to predict their patients' chances of prostate cancer recurrence and to tailor the treatment plan. The results also indicate that drugs might be developed to suppress Pin1 levels, possibly preventing disease recurrence and further helping doctors manage what is now the most common cancer among American men.
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New Approaches to Therapeutics
Hot Flash Drug May Interfere with Cancer Therapy
Tamoxifen (Nolvadex®) is an effective therapy for some types of breast cancer. However, roughly 80 percent of women who take the drug experience hot flashes. While not life-threatening, hot flashes can be so uncomfortable that people stop taking the medicine. To make this cancer-controlling drug tolerable, doctors can treat Nolvadex-triggered hot flashes with antidepressants such as paroxetine (Paxil®).
New evidence hints that taking both drugs together may not be such a good idea. David A. Flockhart, M.D., Ph.D., of the Indiana University School of Medicine in Indianapolis knew that the body uses the same enzyme to break down Nolvadex and Paxil. He therefore wondered whether taking both drugs together might affect blood levels of either or both of them. To test this, Flockhart performed a study with 12 breast cancer survivors who had been taking Nolvadex for at least 1 month and were having severe hot flashes. He gave Paxil to the study volunteers for 4 weeks and then took blood samples.
Women who took both drugs at the same time had substantially lower levels of a key byproduct of Nolvadex, chemical evidence that Paxil does affect how the body processes Nolvadex. But the effects differed among the women depending on their innate capacity to process drugs, which helps explain why Nolvadex's effectiveness can vary among people. Flockhart cautions that further data are needed to determine if treatment recommendations should be altered as a result of his study.
Bone Marrow Cells Help Heal Wounds, Maintain Skin
The body springs into action to heal a wound. Cells in the bloodstream muster to form a clot and fight infection. Researchers have long known that the infection-fighting cells are produced in the bone marrow. But recently, they discovered that cells from the bone marrow also play a role in healing wounds and maintaining normal skin.
Frank Isik, M.D., of the University of Washington Medical Center in Seattle tracked the fate of bone marrow cells by using mice whose cells were engineered to glow green under a fluorescent light. He transplanted green-glowing bone marrow cells from these mice into another set of mice, which were genetically identical except that they lacked the green fluorescent protein. He then inflicted a small wound in the skin of the transplanted mice's backs. To his surprise, as long as 6 weeks after the mice had been wounded, well after infection had ceased to be an issue, green-glowing cells derived from the bone marrow remained in their healed skin.
Probing further, Isik found that only the bone marrow-derived cells produced a particular type of collagen that is found in skin throughout the body, not just in healed wounds. This led him to conclude that cells from the bone marrow help form the tough, yet expandable, matrix of the skin. Isik now wonders whether diseases that interfere with wound healing, such as diabetes, do so because they affect bone marrow cells. In time, this line of research may reveal targets for drugs that will promote wound healing.
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Promising Technologies
Sweeter Opportunities in Carbohydrate Research
Carbohydrates are not just a much-maligned food group—they are vital to all living systems. They take part in everything from communication between cells to the immune response, growth, and brain function. Made up of long, often highly branched chains of sugar molecules, carbohydrates are notoriously difficult for researchers to work with. As a result, the molecules are not nearly as well understood as DNA or proteins. Three recent advances reveal new insights into how carbohydrates work and how researchers can work with them. These findings promise to open new ways to diagnose and treat a host of diseases.
Ajit Varki, M.D., of the University of California, San Diego, has unexpectedly found that the carbohydrates people eat can actually infiltrate into their cells and may increase the risk of certain diseases. Previously, scientists believed that ingested carbohydrates were broken down into simple building blocks and that cells contained only carbohydrate molecules that the body synthesized from these smaller compounds.
Varki studied a carbohydrate molecule that is present in high levels in red meat and milk. Although humans do not make this carbohydrate, Varki had earlier found small amounts of it in human tissues. He has now shown that the source is meat and dairy products and that the molecule, which the body recognizes as alien, provokes an immune response that he believes could cause long-term inflammatory reactions in body tissues.
Eating large quantities of red meat has been linked to heart disease and some forms of cancer, and recent research suggests that meat in the diet may increase the risk for some autoimmune diseases like rheumatoid arthritis. Although most scientists think the primary culprit for such associations is saturated fat, Varki speculates that an immune response to foreign carbohydrates might also contribute.
Carbohydrates, like the one Varki studied, often coat the surfaces of cells, where they are crucial to cell interactions. Using a specially designed cell-surface carbohydrate, Carolyn Bertozzi, Ph.D., of the University of California, Berkeley, has accomplished the feat of tagging certain cells in living mice.
First, Bertozzi injected mice with an artificial carbohydrate that wended its way through their bodies, finally lodging on the outer surfaces of their cells. Then she fed the mice a chemical that reacts specifically with the synthetic carbohydrate but nothing else in their bodies. Taking advantage of the light-absorbing properties of the chemical tag, Bertozzi confirmed that the chemical had reached and reacted with the artificial carbohydrate, without causing any harm to the mice.
Bertozzi's ability to customize the carbohydrates on cell surfaces represents a powerful new way to study the molecules and promises a wide range of clinical applications, such as potentially tagging cancer cells with lethal chemicals.
To capitalize on opportunities like the one provided by Bertozzi, biotech and pharmaceutical companies will need to be able to synthesize carbohydrates efficiently. Currently, the process is labor-intensive and time-consuming. In a chemical tour de force, David MacMillan, Ph.D., of the California Institute of Technology in Pasadena developed a new method for building carbohydrates that is simple and straightforward, requiring just two steps. This technique will revolutionize the study of carbohydrates and could be used to produce a wide range of drugs and diagnostic tools, including those targeting the heart, immune system, and brain.
Still the most mysterious of biology's big molecules, carbohydrates have always been just as important as proteins and DNA to the lives of cells. Now, through these recent advances in tracking, customizing, and synthesizing carbohydrates, scientists are poised to understand the molecules better and use them in new medical applications.
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Designing and Building Proteins Gets Easier
You may not be able to judge a book by its cover, but you can judge a protein by its shape. The three-dimensional structure of a protein, which is made of amino acids, enables it to latch onto other molecules, triggering a host of chemical reactions. When these reactions fail to occur properly, scientists search for the protein structure responsible. While they can easily determine a protein's amino acid sequence, scientists cannot reliably predict how this sequence will fold into a protein with a certain shape and function.
Given this problem, some researchers have decided to work backwards. Rather than starting with a sequence, David Baker, Ph.D., of the University of Washington in Seattle started with a structure. In groundbreaking research, he showed that it is possible to design and build a protein with a specific shape. He sketched a protein structure that had never before been observed and then used a computer modeling program he had created to predict the amino acid sequence that would form the new molecule. Baker used that sequence to build an actual protein that was stable and quite similar in structure to the one he had drawn.
With this ability to create a protein made to order, Baker's research offers a promising new route for developing custom proteins that could be used as drugs or molecular machines to interrupt or enhance a particular reaction inside a cell.
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