By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Two adult mice face each other close up and personal in the photograph. The question is: Which mouse is older?
The dapper animal on the left has smooth brown fur, bright eyes and a snout that points straight ahead. Terminal scruffiness describes the coat of the rodent on the right. Its head droops way down, its nose almost touching the floor. Its eyes look veiled and dull. Its backbone bulges at the neck in what gerontologists call a ¿dowager¿s hump¿ ¿ the post-menopausal spinal curvature that often marks old age in both sexes.
Yet that geriatric-looking mouse is younger ¿ by a month ¿ than its sleeker, opposite number. What accounts for this accelerated murine superannuation? It¿s the ku80 gene. Knocking it out sped up the aging process in the right-hand mouse. KO mice live an average of nine months, compared with the normal murine life span of two years.
This photo does not adorn the June 2000 issue of the monthly journal, Molecular and Cellular Biology (released May 10). However, the animals in question are featured in its article titled: ¿Analysis of ku80¿mutant mice and cells with deficient levels of p53.¿ The co-authors are a joint team of scientists from Lexicon Genetics Inc. in The Woodlands, Texas; Baylor College of Medicine in Houston; and the University of Washington in Seattle.
Their report reveals the key part that Ku80, the protein the gene expresses, plays in the aging process, and its links to cancer via the p53 tumor suppressor ¿ the most commonly mutated gene in human malignancy. Ku80 normally repairs sequence breaks in double-stranded DNA.
Lexicon, which holds the five basic patents covering all knockout mice, received a U.S. patent in September protecting its proprietary ku80 KO mouse. Since then, its latest studies show that the ku80 gene not only controls the rate at which animals grow old, but also exerts its senescing effects through a pathway with the p53 tumor suppressor gene¿s function.
¿Our Ku80 KO mice show distinct signs of early onset of aging, bone weakness, thinning of the skin, hair loss and susceptibility to infection,¿ said the paper¿s senior author, Paul Hasty. He is Lexicon¿s director of DNA repair research. ¿Our work,¿ he continued, ¿demonstrates that the processes of aging and cancer formation are separate yet interrelated at a molecular level.¿
The co-authors crossed mice lacking the ku80 gene with animals lacking the p53 gene. They found that cells from these double-knockout animals did not age prematurely ¿ but the animals still developed cancer.
¿Lexicon scientists,¿ said the firm¿s president and CEO, Arthur Sands, ¿are studying the fields of cancer and aging using KO technology in a high-throughput mode. Our immediate activity,¿ he told BioWorld Today, ¿is to identify additional targets on the Ku and p53 pathways, using these unique ku KO animals to find those genes that affect the aging and cancer process.¿
Human Cytomegalovirus Forces Cells It Infects To Fly All¿s Well¿ Flag ¿ Duping Defenses
Cytomegalovirus (CMV) is a herpes virus that infects 90 percent of the human population ¿ in most people inflicting no symptoms. But CMV can cause a variety of infections, particularly in infants and immune-deficient people, notably AIDS patients. New research in Britain has unmasked a devious tactic that CMV deploys to hold its victims¿ immune defenses ransom.
UK scientists at the University of Wales College of Medicine in Cardiff, and at John Radcliffe Hospital in Oxford, report discovering that once the virus infects a cell, it forces that cell to express on its surface a lot of so-called HLA-E proteins (HLA stands for ¿human leukocyte antigen,¿ which defines the body¿s immune type). Its HLA-E subtype has the job of patrolling the body to sniff out infectious invaders.
Like a medieval town crier, HLA-E signals ¿all¿s well¿ to the immune system¿s natural killer cells, hunting for CMV-infected cells to destroy. But by bullying those cells into expressing those protective HLA-E proteins on its surface, the virus succeeds in evading detection and destruction.
The report appears in Science dated Feb. 11, 2000, under the heading: ¿Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40.¿
Four New Takes In Three Weeks Groom Adeno-Associated Virus As Ideal Gene Therapy Vector
Adenoviruses (AV) make great DNA-delivery vectors for gene therapy. Great, in the sense that their roomy sequences are big enough to carry sizeable genes of interest. But the downside of AVs ¿ which spread the common cold ¿ is the concern that this virus may also trigger harmful immune responses.
So gene therapists have been pinning their hopes on AV¿s little viral brother, the adeno-associated virus (AAV). It inflicts no pathogenicity whatsoever, despite its ability to act only in the presence of AV. But AAV¿s drawback is its relatively small carrying capacity ¿ not nearly capacious enough to transfer the genes for such diseases as cystic fibrosis, hemophilia A and some types of muscular dystrophy. To circumvent this one-size-won¿t-fit-all handicap, gene therapists at Stanford University in California have split their gene of interest into two parts, and packaged each half into a separate recombinant AAV vector. Their report in Nature Biotechnology for May 2000 tells its own story, titled: ¿Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors.¿
At the University of Iowa, scientists hit upon the same AAV-splitting stratagem, as reported in the May 2000 issue of Nature Medicine, under the title: A new dual-vector approach to enhance recombinant adeno-associated virus-mediated gene expression through intermolecular cis activation.¿
In the same issue of Nature Medicine, molecular geneticists at the University of Pittsburgh weighed in with their version of the trick, titled: ¿Overcoming adeno-associated virus vector size limitation through viral DNA heterodimerization.¿
Finally, a different spin on the AAV challenge appears in the current Proceedings of the National Academy of Sciences (PNAS), dated April 25, 2000. Its title: ¿Adeno-associated virus site-specifically integrates into a muscle-specific DNA region.¿