Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
Two back-to-back papers on neural stem cell research, by the same senior author, Harvard neuroscientist Evan Snyder, appear in Nature Biotechnology for November, dated Oct. 15, 2002. (See BioWorld Today, Oct. 17, 2002, p. 1.)
The second study bears the title: "Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons."
It asks whether the stem cells are effective against the slow degeneration of brain function in mice treated with chemicals to mimic the process of aging or Parkinson's disease in people. Surprisingly, the transplanted cells were found to rescue damaged host cells, stimulating them to produce more of the enzymes essential for dopamine activity.
"This paper," Snyder told BioWorld Today, "enunciates a whole new, novel third mechanism of stem cell action - at least from the therapeutic point of view. The first two actions that everybody talks about with pluripotent stem cells are that they replace the missing cells, or using them for gene therapy.
"This for the first time announces a third new mechanism that we think is very powerful. It says a stem cell will rescue the damaged cells of an animal or a patient. Here we used a disease model that really emulates most of the degenerative nerve diseases that one sees. It slows the dissolution of function over time, as opposed to just repairing an acute CNS [central nervous system] injury. But most degenerative diseases in any organ system see the system gradually falling apart - and then it dies.
"For example," Snyder continued, "Hodgkin's disease, aging, all of the brain diseases, are clearly like that, but even those of other organ systems are, too. And we show in this article that the neural stem cells can rescue these cells even without replacing them, not having to put foreign genes into them. The stem cell itself is just playing out its fundamental biology. That is, it can serve to rescue cells even though it doesn't convert to become the missing cells. It does this robustly and in a powerful way, maybe using that mechanism, even more powerfully than the other two CNS stem cell mechanisms that heretofore have gotten most of the attention.
"And we see the same story as applicable to stem cells of many organ systems and in many other organs. Maybe even the mechanism explains sometimes-weird results," Snyder concluded, "that people try to report, where they see things getting better far beyond what the stem cells seem to have been able to do."
Atomic Structure Of High-Profile Farnesyl Enzyme Widens Path To Cancer Therapy
A lipid-modifying enzyme, farnesyltransferase (FTase), has emerged as a promising target for cancer therapy. More than 300 patent applications have been made so far for FTase inhibitors, and six or more are currently in clinical trials. FTase catalyzes the attachment of a farnesyl lipid group to signal transduction proteins - including the ras oncogene, which is implicated in nearly a third of human malignancies.
Structural biochemists at the Duke University Medical Center in Durham, N.C., have now determined the enzyme's reaction path. They describe two possible sites of action for FTase inhibitors. Their paper in Nature dated Oct. 10, 2002, is titled: "Reaction path of protein farnesyltransferase at atomic resolution." The authors "present a complete series of structures representing the major steps along the reaction coordinate of this enzyme. From these observations can be deduced the determinants of substrate specificity and an unusual mechanism, analogous to classically processive enzymes.
"The structural details of the FTase reaction pathway presented here," they continue, "suggest that clinically active anticancer FTase inhibitors may have at least two primary modes of inhibition: blocking the substrate peptide site and, unusually, blocking the exit groove." Their paper concludes on an interesting tangent: "There is therefore ample opportunity for the design of additional drugs that are targeted to binding in the exit groove sites. These strategies may become important in the design of drugs that specially target pathogens such as Plasmodium falciparum - the malarial parasite - and do not bind to human FTase."
Hitherto Unknown Enzyme Reported Guilty Of Familiar Tear-Provoking Chopped Onions
Just as the neurotoxin capsaicin drives the burning sensations generated by red-hot chili peppers, a newly discovered enzyme accounts for the weeping eyes resulting from chopping onions.
A one-page "Brief Communication" in Nature dated Oct. 17, 2002, carries the double-barreled headline: "An onion enzyme that makes the eyes water: A flavorsome, user-friendly bulb would give no cause for tears when chopped up." Its authors are at the University of Tokyo and the House Foods Corp. in Chiba, Japan.
Their paper leads off: "The irritating lachrymatory factor that is released by onions (Allium cepa) when they are chopped up has been presumed to be produced spontaneously following the action of the enzyme allinase, which operates in the biochemical pathway that produces the compounds responsible for the onion's characteristic flavor. Here we show that this factor is not formed as a byproduct of this reaction, but that it is specifically synthesized by a previously undiscovered enzyme, which we have named lachrymatory-factor synthase."
The new-found molecule's full-length cDNA (in GenBank) consisted of 737 base pairs, with a predicted gene product of 169 amino acids. The paper indicates "that it might be possible to develop a non-lachrymatory onion by suppressing the gene while increasing the yield of thiosulphinate, which is responsible for the flavor of fresh onion." The authors' finding may one day lead to tear-free, genetically modified onions, with the novel enzyme deleted. Because flavor compounds are not involved with the new enzyme's reaction, the team proposes, such a modified onion should taste as good as the original.