By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Contriving antibodies to vaccinate people against Alzheimer¿s disease (AD) has become a brisk infant industry in the neuroimmunology community. Here are some of the main ducks to line up in a row in attempting to advance this novel goal:
¿ The logical antigenic target of such a vaccine is a 40- to 42-amino-acid peptide called amyloid-beta (Ab). This is the smoking gun of AD, in that it is a prime ingredient of the senile, neuritic amyloid plaques that wrap around the moribund brain neurons in the disease. Indeed, the definitive diagnostic test of whether a dementia is or is not true Alzheimer¿s is the presence of these plaques in the postmortem brain. The runty Ab is spun off from a much longer molecule, amyloid precursor protein (APP).
¿ A monoclonal antibody directed against the central domain of the amyloid-beta peptide¿s sequence.
¿ A transgenic mouse model to develop and test the putative AD vaccine. Such a faithful mimic of the disease pathology generates Ab within the central nervous system (CNS), adjacent to the brain.
These experimental elements inform a paper in the Proceedings of the National Academy of Sciences (PNAS) dated July 17, 2001. Its title: ¿Peripheral anti-Ab antibody alters CNS and plasma Ab clearance and decreases brain Ab burden in a mouse model of Alzheimer¿s disease.¿ Its senior author is neurologist David Holtzman at Washington University School of Medicine in St. Louis. Other co-authors include investigators at the Eli Lilly & Co. Research Laboratories in Indianapolis.
The AD-mimicking mice were divided into three cohorts: Those receiving intravenous injections of the Ab antibody, and two controls, which got a dummy antibody or saline solution. ¿Within hours of injecting the antibody into mice,¿ Holtzman recounted, ¿the concentration of amyloid-beta in the bloodstream rose approximately 1,000 times higher than before the treatment.¿ He construed that ¿the antibody was binding all the amyloid-beta in the blood, as well as additional amyloid-beta as it entered the blood from the brain. The antibody,¿ he added, ¿appeared to be facilitating the removal of amyloid-beta from the brain into the blood.¿
This result supported the theory that mice immunized with the antibody over a period of months developed fewer amyloid plaques in the brain than did control animals. The antibody remained in the animals¿ bloodstream and did not react directly with amyloid plaques in brain tissue.
The co-authors are now investigating the detailed mechanism of how the antibody exerts its effects. They suggest that this project has implications for both diagnosis and therapy of Alzheimer¿s disease.
Recruiting Ras Pathway Aims To Turn Herpes Virus From Infecting Skin To Fighting Cancer
Almost everyone on earth harbors herpes simplex viruses (HSV) in his or her body. Most of the time, these viral pathogens hibernate in dorsal root ganglia of the nervous system, waiting to pounce. When HSV type 1 (labialis) wakes up, it raises blisters on lips. Type 2 (genitalis) inflicts painful, chronic ulcers on male and female genitalia.
Now Canadian virologists and oncologists at the University of Calgary, Alberta, are trying to turn the cold-sore HSV around, as a model virus to fight cancer. Their paper in the August issue of Nature Cell Biology is titled: ¿Oncogenes in Ras signaling pathway dictate host-cell permissiveness to herpes simplex virus 1.¿ Its senior author is virologist and cancer biologist Patrick Lee.
The Ras ¿ reticular activating system ¿ pathway is a major biochemical pathway that controls cell growth. In the majority of tumor cells, Ras is highly activated, resulting in uncontrolled cell proliferation. Healthy cells tightly curb Ras.
¿We finally understand how the herpes virus invades cells,¿ Lee told BioWorld Today. ¿That will allow us to more effectively manipulate herpes and other viruses as powerful tools to kill cancers.
¿In normal cells that are resistant to herpes infection,¿ he explained, ¿the virus gets into the cell. There the viral transcript can activate PKR, a protein kinase. By so doing, the virus essentially commits suicide, because PKR, when activated, blocks RNA translation. Ras can prevent this from happening.
¿In order for an infection to occur,¿ Lee continued, ¿two tools are needed: one, the virus carries its own anti-PKR tool, via a gene; and two, it also requires the target cell to act as an anti-PKR agent. That is the Ras pathway. One from the viral arm, the other from the cell arm. And both are doing the same thing ¿ preventing PKR activation.
¿If we knock out the viral anti-PKR arm,¿ Lee went on, ¿then it would need the cell arm to compensate. This novel concept is how we propose to generate a cancer killer.¿
From Treasure Chest To Pandora¿s Box: Homeless Genes In Bacterial Genomes
Genes of unknown function tantalize molecular geneticists plowing the rich soil of the expanding list of totally sequenced genomes. Biomedical engineers at Boston University applied fusion link analysis to 30 complete bacterial genomes. Their approach establishes a relationship between two separate, distinct genes in an organism by finding an instance where these genes are fused or linked together as a continuous sequence in another organism. They found that 72 percent of the time such links do indeed relate genes of the same functional category.
One of the co-authors¿ 661 predictions published on the web dissects the gene relationships of the archaic Methanobacterium thermoautotrophicum.
Their paper in the Proceedings of the National Academy of Sciences (PNAS) dated July 3, 2001, is titled: ¿Genes linked by fusion events are generally of the same functional category: A systematic analysis of 30 microbial genomes.¿