A master trickster virus called VSV has baffled scientists for quite some time. Because VSV is a true expert at sneaking into cells, it is widely used in gene therapy and might, in the future, help to treat cancer. Yet even though it’s been employed in research and in pre-clinical studies for over 30 years, how it gets into cells has remained a mystery. Weizmann Institute scientists have now solved this riddle, as reported in the Proceedings of the National Academy of Sciences (PNAS).

 

VSV is particularly suitable for research and therapeutic use because, although it causes disease in farm animals, it rarely does so in humans. Yet the virus is so good at penetrating human cells that scientists commonly use it in experimental gene therapy as a vehicle to deliver desired genes to cells. In addition, VSV holds promise for use in cancer therapy because it selectively kills cancer cells.

 

 

 

 

 

 

 

 

 

 

 

 

 

“Biologists live in hope of discovering 'textbook examples’,” says Dr. Maya Schuldiner of the Molecular Genetics Department. To demonstrate, she opens a biology textbook and points to a diagram of a molecular pathway – a series of molecular interactions for getting a cellular protein or process from point A to point B. Since many proteins tend to use the same general molecular pathways, a textbook example should ideally reveal important insights into the working of a cell, and it may often generate reams of further study and discovery.

But textbook examples, says Schuldiner, are hiding a much more complex reality: “Generally, the pathways that are discovered first are assumed to be the most important. When we start finding proteins using other pathways, we call these ‘exceptions to the rule.’ Often, no one stops to ask how many proteins actually use one pathway or another.”

Schuldiner and research student Tslil Ast decided the time had come to ask that question. It was time, in part, because new technology would enable them to check many proteins at once: The high-throughput microscopy equipment and computational techniques used in Schuldiner’s lab are able to reveal the pathways of hundreds of cellular proteins in a fraction of the time formerly required to study just one or two.  
 

 

 

 

Blocked or constricted blood vessels lead to high blood pressure, heart attack and stroke – some of the most common causes of death in the Western world. Blood vessels become blocked when fat is deposited on artery walls, building up until the flow of blood is restricted and the delivery of oxygen and nutrients curtailed. Today, such “clogged pipes” are cleared with drugs, angioplasty or bypass surgery to replace the blocked sections. But in the lab of the Weizmann Institute’s Dr. Karina Yaniv, researchers are looking for ways to keep the body’s main conduits from getting clogged up in the first place.

 

To prevent blockages, one must understand exactly how they occur. As opposed to the kitchen drainpipe, which gets clogged from the passive accumulation of gunk, the deposition of fat on blood vessel walls is an active process in which the cells lining those walls can sense fats carried in the bloodstream and respond according to amount and type. According to Yaniv, that fat and those vessel-lining cells – endothelial cells – engage in a two-way conversation that facilitates the fat build-up. Basically, the endothelial cells give the fat permission to cross the inner layer of the “pipe” to settle comfortably on the other side of that layer. As the fat layer grows, it presses on the blood vessel walls, constricting them and creating the conditions for blood vessel disease.

 

How does LDL or its lack affect the growth of new blood vessels? The researchers found that lowering the bad cholesterol levels resulted in an increased division of the endothelial cells, while raising LDL levels had the opposite effect: Cell division was delayed, as was the cells’ ability to migrate and contribute to the formation of new blood vessels. Further investigation revealed that LDL directly interferes with a main mechanism of endothelial cell proliferation, in which a growth factor called VEGF binds to the cell surface to activate the process. VEGF can bind to two different types of receptors on the cell. The first is the “regular” receptor, which responds to VEGF binding by initiating cell proliferation. The second is a “dummy” receptor, which binds but does not initiate division. The dummy receptors are a sort of double-check and regulation mechanism, but LDL appears to encourage the production of this type of receptor. Thus high LDL levels mean more of the dummy receptors and less endothelial cell proliferation, while low levels promote cell division and, thus, the creation of new blood vessels.
  

 

To die or not to die: That is the question all living cells face at some point in their lives. How this dilemma is ultimately resolved can have crucial consequences for our health. When cancer cells refuse to die, having developed a resistance to drugs, chemotherapy becomes ineffective. On the other hand, Parkinson’s disease and other neurodegenerative disorders occur when certain neurons in the brain die too readily. Understanding the precise mechanics of the major cellular death program, called apoptosis, is therefore essential for developing treatments for a variety of diseases.

Crucial new information about apoptosis has emerged from a Weizmann Institute study published recently in the Journal of Cell Biology. Dr. Eli Arama of the Molecular Genetics Department and Ph.D. student Anat Florentin have found a mechanism that makes some cells more sensitive to apoptosis than others, and they have established, in great detail, how the final stage of the cellular death program works.

Apoptosis can be triggered by a variety of signal sequences, but the final link, the “weapon” that performs the actual killing of the cell, is always the same: It consists mainly of utterly destructive enzymes – the effector caspases – which kill the cell by chopping up hundreds of cellular proteins. Until recently it was known that in mammalian cells two such enzymes, caspase-3 and caspase-7, were intimately involved in apoptosis, but their distinct roles in this process were unknown. Working with fruit flies, which have enzymes similar to the human caspases – Drice and Dcp-1, respectively – Arama and Florentin have produced a series of findings that make it possible to draw conclusions about the two mammalian caspases.