By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
It takes real oomph for a newly fledged butterfly to pull itself out of its cocoon. Then, before it can take off in flight, the winged insect has to rid itself of the now-redundant muscles that liberated it from its larval integument. But shucking off those now-useless muscle cells isn't as simple as an airplane dropping an empty fuel tank.
Instead the butterfly resorts to programmed cellular suicide - apoptosis.
In the world of vertebrates, apoptosis is a constant component of homeostasis, the ubiquitous process that keeps every bit of the body on an even keel. For example, the white cells in the circulating blood of an adult human consist of about 60 percent of immune-system neutrophils. Those 50 billion cells have a life span of one day, after which they die by apoptosis, and are replaced.
Apoptosis - programmed cell death - proceeds by collapsing the target cell's nucleus into small fragments, which are phagocytosed, or digested, by the immune system's scavenger cells, including neutrophils themselves. That's how the body routinely rids itself of virally infected or mutated (notably cancerous) cells.
Most cells in the mammalian body express on their surface a receptor protein called FasLigand (FasL). Fas signals its cell-death verdict upon stimulation by FasL or an agonistic Fas antibody. Immunologists refer to FasL as "Doctor Death," because it triggers the normal turnover decreed by apoptosis. Two immune-privileged tissues in particular - retina and testes - evade this assisted cell suicide. Their strategy is to coat their cell surfaces with a high-density overlay of FasL. When an apoptosis-bent B cell or T cell attacks, those FasL molecules cross-link, which condemns the immune cell itself to commit programmed cell death hara-kiri.
Many malignant tumors borrow a leaf from this same hymnbook, to frustrate apoptotic assault by chemotherapy or by the immune system's surveillance of mutated tumors. High on this rap sheet of artful dodgers is colorectal cancer, which will result in an estimated 135,400 new cases in the U.S. this year, and kill 56,700 patients with the disease.
About half of the top 50 economically developed countries in the world have higher death rates from colorectal cancer than does the U.S., which is at the midpoint - as is Japan. Japanese scientists at the Daiichi Pharmaceutical Co. Ltd., in Tokyo, announced this month that they have identified a novel protein, which enhances anticancer apoptosis via Fas.
Their paper, in the January 2001 issue of Nature Medicine, is titled: "SADS: A new component of Fas-DISC is the accelerator for cell death signaling and is down-regulated in patients with colon carcinoma." The co-authors named their protein SADS, standing for "small accelerator for death-signaling," because it speeds up Fas-mediated apoptosis.
Honchoing this cascade are proteolytic enzymes called caspases. Fas goes to work when procaspase-8 is recruited to DISC - a "death-induced signaling complex" via FADD - a "Fas-associated protein with death domain."
SADS is expressed in a number of high-turnover human cell types, the Daiichi team noted, including colon, thymus, spleen and small intestine. They found that their SADS protein's expression is lost in some human colon cancer cells. Surgical tissue samples from colon cancer patients in which SADS protein synthesis was down-regulated resisted cell death. In contrast, when these cell lines were transfected with SADS cDNA, they became sensitive to Fas-mediated apoptosis. Their data suggested that SADS acts as a death accelerator, rather than a direct death inducer.
"SADS expression led cells to suicide by contact inhibition," their Nature Medicine paper concluded. "This strongly indicates that in future, SADS can be effectively used for tumor gene therapy in patients with colon carcinoma."
Extract Of African Trial-By-Poison Bean Tested In Memory-Enhancing Drug Brain-Scanned By MRI
In bygone centuries, the coastal Nigerian town of Calabar was a major depot of the African slave trade. It gave its name to the poisonous Calabar bean (Physostigma venenosum), which became known to Western traders through its role in the native judicial trial by poison. Persons accused of offenses had to ingest the beans. Toxic symptoms confirmed guilt; upchucking the poisonous seed, innocence.
Nowadays, the alkaloid drug physostigmine, extracted from the bean, is used for treating glaucoma and myasthenia gravis, as well as enhancing failing memory in Alzheimer's disease patients. It's an inhibitor of the brain's neurotransmitter enzyme, acetylcholinesterase. So are the modern synthetic pharmacological agents used to counteract cognitive dysfunction, which have longer half-lives and fewer side effects.
Recently, scientists at the Laboratory of Brain and Cognition at NIH's National Institute of Mental Health (NIMH) in Bethesda, Md., conducted a different kind of trial with physostigmine (which blocks the breakdown of acetylcholine) in seven young human volunteers. Their double-blind, placebo-controlled, cross over study took place on two separate days. On day one, they received intravenous infusions of the drug; on day two, placebo saline. Their "ordeal" was to memorize and recall a battery of faces, shown on photographs.
An NIMH report of the experiment in Science dated Dec. 22, 2000, bears the title: "Cholinergic enhancement and increased selectivity of perceptual processing during working memory." At each test session, a picture of a face was presented for 3 seconds (encoding phase), followed by a 9-second pause (during which the image was "held" in working memory), followed by a 3-second exposure of two different faces. Subjects indicated which of the two they recalled having seen previously by pressing right or left response buttons with their thumbs. Magnetic resonance imaging (MRI) scanned these short-term memory reactions to the relevant participating brain regions.
"Infusion of physostigmine," the paper reported, "resulted in enhanced neural processing in visual cortical areas." It concluded: "Deterioration of the cholinergic system contributes to memory failure and cognitive decline in Alzheimer's disease and also may play a role in the more benign memory changes associated with healthy aging."
An accompanying commentary by experimental psychologists at the University of Cambridge, UK, observed: "The precise relationship between working memory and different regions within the prefrontal cortex is currently the subject of intense debate." They added that such studies "raise the exciting possibility that aspects of working memory may be improved by drugs with selective actions on different neurotransmitter systems."