Archive Site Provided for Historical Purposes
Sponsored by the U.S. Department of Energy Human Genome Program
In this issue...
In the News
Special Meeting Report
Web, Publications, Resources
Meeting Calendars & Acronyms
A new technique for detecting proteins associated with prostate cancer may serve as a sensitive assay for this common killer and have wide applications beyond diagnostics as well. The work was reported in the September 2001 issue of Nature Biotechnology [http://www.nature.com/nbt/journal/v19/n9/full/nbt0901-856.html] by a team of researchers led by Thomas Thundat (Oak Ridge National Laboratory), Arun Majumdar (University of California, Berkeley), and Richard Cote (University of Southern California).
The new instrument induces cancer-associated proteins known as prostate-specific antigens (PSAs) to stick to and ultimately bend a cantilever that measures one-hundredth the width of a human hair and looks like a tiny diving board. When proteins bind to the surface, the microcantilever bends and a sensitive laser detects and measures the minute movement, thus signaling the presence and amount of increased levels of PSA. Although the cantilever moves only about 10 to 20nm, lasers can detect a deflection as small as a fraction of a nanometer. The researchers report that the instrument is sensitive enough to detect PSA levels at 5% of the clinically relevant threshold and at potentially much lower cost than the conventional assay. A commercial application may be available within 3 to 5 years.
Thundat won a Discover Magazine award for the use of microcantilever sensors in detecting land mines. This technology can be applied to the detection of chemical and biological threat agents, environmental pollution (volatile organic compounds and groundwater contamination), and cations such as calcium in biological fluids, proteins, DNA, and DNA SNPs. It also can be used for night-vision cameras, thermal spectrometers, viscosity meters, and flow-rate meters.
The many and varied applications of this technology illustrate the cross-disciplinary nature of the national laboratories, including their unanticipated value to bioscience and human health. The research is supported by the DOE Office of Biological and Environmental Research and Office of Basic Energy Sciences and the NIH National Cancer Institute. (http://www.science.doe.gov/Science_News/feature_articles_2001/ october/Cancer-detecting/ Cancer-detecting-microchip.htm).
Cells can respond to stresses by entering a state of arrested growth and altered function known as senescence, which may have evolved as a check against tumor growth. New findings by researchers at Lawrence Berkeley National Laboratory (LBNL) indicate that in older organisms, senescence promotes rather than inhibits cell proliferation and may contribute to the much higher rates of cancer in older people.
In a paper published in the October 9, 2001, issue of the Proceedings of the National Academy of Science, Judith Campisi and colleagues report that injecting mice with senescent human fibroblast cells and mutated epithelial cells results in tumor formation in the animal. The LBNL researchers propose that interactions between epithelial cells lining the ducts, glands, and surfaces of organs and the stromal fibroblast cells that support and maintain them are key to the progression from cancer-prone, mutated cell to full-blown tumor. Senescent fibroblasts exhibit dramatic changes in gene expression and secrete many molecules that can alter the environment surrounding cells. As senescent cells accumulate with age, the altered microenvironment may facilitate the progression and proliferation of mutant cells to tumors. Although other events contribute to late-life cancers, they note, stromal changes may be of particular importance to humans because most age-related cancers such as breast and prostate arise from epithelial cells (www.lbl.gov/Science-Articles/archive/senescence.html). The work was supported by a grant from the National Institutes of Health.
Cells with the same genetic material are observed to behave very differently when confronted with different microenvironments. In an article appearing in the October 2001 issue of Nature Reviews Cancer, Mina Bissell and Derek Radisky (LBNL) note that the association of cancer cells with their surrounding tissues forms a new tumor context that changes to maintain the functional disorder as malignancy progresses (www.nature.com/nrc/). The microenvironments of cancer cells thus are powerful and insidious carcinogens that also must be targeted in therapeutic regimens. Investigation into the mechanisms of tumor formation (tumorigenesis) can lead to next-generation combination therapies that not only inhibit and destroy tumor cells but also normalize the microenvironment (www.lbl.gov/LBL-Programs/lifesciences/BissellLab/main.html).
Expected to Guide Drug Development
Understanding the 3-D structures of proteins can provide clues to the roles they play in living organisms. A landmark study by an international team using the Advanced Photon Source (APS) at Argonne National Laboratory has solved for the first time the structure of a protein thought to have a significant function in tumor growth, bone maintenance, and inflammation. It may even be involved in enabling infection by the viruses responsible for AIDS and foot-and-mouth disease (Science 294, 33945).
Integrins are proteins found in cell membranes that control many cellular processes and also serve as a channel through which viruses can enter and infect cells. These proteins have proven extremely difficult to isolate and crystallize in preparation for determining their 3-D structures. The structure revealed by the APS is a complicated one, with 12 distinct regions (domains) arranged in the shape of a propeller. Researchers hope this new information will help biologists understand how integrin transmits its signals and will guide drug design.
Researchers at Sandia National Laboratories announced the creation of a micromachine that operates on the minute scale of cells. The new device features silicon teeth that open and close like jaws to capture and release human cells, which appear unharmed by the process. The machine fits into a microchannel about one-third the width of a human hair and can be mass-produced easily and cheaply through computer-chip production techniques. The ultimate goal of the device is to puncture cells and inject them with DNA, proteins, or pharmaceuticals to counter biological or chemical attacks, gene imbalances, and natural bacterial or viral invasions. Although the prototype tool traps red blood cells, the machine also may be used to hold stem cells for possible gene implantation or other alterations. Developers note that the ability to implant materials in cells has important implications for the multibillion-dollar microfluidic device industry, currently capable of analyzing biofluids but not altering them (www.sandia.gov/media/NewsRel/NR2001/gobbler.htm).
LBNL researchers report the discovery of a new human gene that affects triglyceride levels in the blood and may influence an individuals risk of developing cardiovascular disease. The gene encodes a member of the apolipoprotein (APO) family of proteins that transport cholesterol, triglycerides, and other blood lipids in the body. The findings may lead to the development of tests to detect susceptibility to hypertriglyceridemia and to new methods to reduce risk.The team scanned the region of human chromosome 11 known to contain a cluster of APO genes to find comparable regions in the mouse genome. Results surprised the researchers, who thought all members of the APO family had been identified. By comparing the sequence of the genomes of humans and mice, we have found a genetic jewel that had been missed when the sequence of the human genome alone was analyzed, said Edward Rubin, leader of the study [http://www.sciencemag.org/content/294/5540/169.abstract?sid=70b6378f-c3e7-4148-aff2-69c2704d61fb/] that was reported in the October 5, 2001, issue of Science. Mutations in the gene were shown to influence triglyceride levels in both mice and humans. The next step, he said, will be to look into the mechanism by which gene polymorphisms influence triglyceride levels and try toidentify specific sequence changes leading to lower APO protein concentrations in the blood (http://www.science.doe.gov/Science_News/ feature_articles_2001/october/ Genetic_research/Genetic_Research.htm).
Possible Vehicles for Gene Therapy
Coxsackie viruses can evade detection by human immune systems to infect cells of the heart, brain, pancreas, and other organs. New details of how they gain entry into cells were reported in the October 2001 issue of Nature Structural Biology [http://www.nature.com/nsmb/journal/v8/n10/abs/nsb1001-874.html] by investigators from Brookhaven National Laboratory and Purdue University.
Structures of the virus generated by cryoelectron microscopy of frozen samples reveal molecular-level interactions between virus and receptors on the cells surface. Studies show that viral receptor proteins form pairs on the surface of human cells, with two adjacent proteins attached to each other below the cell membranes surface. When the virus binds to the human cell, it forms bonds with both the pairs receptors. Structural studies also reveal that the binding sites on the virus are hidden from the bodys immune system, which produces antibodies to fight infections. These features are shared with other viruses in the same family. The work may lead to improved ways to thwart viral infections and design virus-based vehicles for gene therapy (http://www.science.doe.gov/ Science_News/feature_articles_2001/ september/How_Some_Viruses/How_Some_Viruses.htm).
In a cover story appearing in the October 18, 2001, issue of Nature, Carlos Bustamente and colleagues at LBNL reported that the DNA inside some viruses is packed so tightly that the internal pressure reaches 10 times that in a champagne bottle. They speculate that this high pressure helps the virus inject its DNA into a cell after it has latched onto the surface. Once inside the cell, the DNA begins retooling the cell to manufacture new copies of the virus.
Such tight packing is achieved by one of the most powerful molecular motors ever observed, stronger than the motors that move human muscles or the nanoscale molecular motors that duplicate DNA or transcribe it into RNA. Measurements were taken using a specialized optical tweezer microscope that allowed researchers to pull on single DNA molecules as they were packaged to determine their resistance to stretching.
A collaboration with scientists from the University of Minnesota, the research was funded by the DOE Biological and Environmental Research program, the National Institutes of Health, and the National Science Foundation.
Bustamentes work has been critical for understanding how biological machines made up of complex parts assemble and control key cellular activities. To recognize his achievements, the American Physical Society awarded him its 2002 Prize in Biological Physics Research, citing his pioneering work in single molecular biophysics and the elucidation of the fundamental physics principles underlying the mechanical properties and forces involved in DNA replication and transcription. The society established the prize in 1982 to recognize and encourage outstanding achievement in biological physics research.
The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v12n1-2).
The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.