By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

More than 18,300 unfortunate people in the U.S. are on waiting lists for a liver transplant. Many of them have been marking time for more than two years. In years to come, this logjam may ease up or go away if an unexpected cell-development discovery pays off.

Endothelial cells are well known as the smooth, seamless lining of blood vessels. Their angiogenesis in mammalian embryos is carried out by embryonic stem cells. These also supply nascent solid tumors with needed blood inputs of oxygen and nutrients. Now scientists at the Fox Chase Cancer Center in Philadelphia report that well before prenatal endothelial cells crank up angiogenesis, they are busy promoting development of the future body¿s visceral organs ¿ notably the liver.

Science published this counter-intuitive finding in a fast-track release dated Sept. 27, 2001 ¿ one day ahead of the journal¿s normal publication date. The paper is titled: ¿Liver organogenesis promoted by endothelial cells prior to vascular function.¿ Its authors, cellular and developmental biologists, found that ¿early endothelial cells in mouse embryos surround newly specified hepatic endoderm and delimit the mesenchymal domain into which the liver bud grows.¿ They developed an embryo tissue explant system that permitted budding liver cells to launch blood vessel cells.

Additional studies showed that this essential role of endothelial cells appeared to extend to lung and pancreas organogenesis. However, when they knocked out these endothelial cells, hepatic outgrowth failed.

¿The new embryonic cell culture techniques we describe,¿ observed the article¿s senior author, Kenneth Zaret, ¿may further future efforts to reconstitute organ systems in vitro, for basic research and drug studies, and within living beings for therapeutic purposes or for artificial organs.¿ His paper suggested in conclusion, ¿The cell interactions that we have discovered during organogenesis may be recapitulated in adult tissues.¿

In a second study, Harvard University scientists used transgenic mice with an overabundance of blood vessel cells, as well as removal of a major blood vessel in frog embryos, to demonstrate that these cells supply signals necessary for the development of the pancreas, and expression of insulin. Their paper in Science, also dated Sept. 27, bears the title: ¿Induction of pancreatic differentiation by signals from blood vessels.¿

Hottest¿ Stem Cell Research Area Uses Statistics To Compare Human, Mouse Cell Turnover In Gut

By comparing differences and similarities of DNA sequences between individuals within a species, scientists can learn a lot about animal populations. Now, reportedly for the first time, they are applying these techniques to the behavior of human stem cells. Thus far, such studies of stem-cell turnover in the intestine have been done in mice, using experimental methods that are impractical in humans. For one thing, the difference in their life span (number of cell divisions); for another, the larger cell counts on human tissues and organs.

To find out how the cells act in people, scientists at the University of Southern California at Los Angeles have come up with a different method. Their report appears in the Proceedings of the National Academy of Sciences (PNAS), fast-track released on Aug. 21, 2001. The paper is titled: ¿Investigating stem cells in human colon by using methylation patterns.¿

The authors isolated stem cell-generated cell populations from the lining of the large intestine, and used statistical methods to analyze nongenetic differences in the species sequences. They demonstrated strong similarities between what occurs in human and in mice stem cells.

An accompanying commentary made the point, ¿Given the importance of cellular population dynamics to a complete understanding of stem cell biology, it is no surprise that cell fate mapping¿ has become one of the hottest areas of stem cell research.¿ They added that the approach detailed in the PNAS paper ¿could provide a new tool for identifying precancerous cells.¿

In Rare FAP Disease, The First Mutant Gene Paradoxically Neutralizes The Second One

The words ¿amyloid disease¿ automatically suggest ¿Alzheimer¿s disease¿ (AD) ¿ and rightly so. But AD is only one of several score amyloid maladies. Its closest counterpart is FAP ¿ familial amyloid polyneuropathy. This rare, inherited nervous-system ailment is caused by misfolding of the protein transthyretin (TTR), known also as prealbumin. TTR, which consists of four separate subunits that bind together, normally circulates in the blood.

This tetramer comes from two different genes on two separate chromosomes. When one of the four copies has a mutant defect, hybrid tetramers form ¿ composed of both mutant and normal subunits, which no longer bind stably. Once turned loose, each subunit can misfold and reassemble into hundreds of misshapen proteins that clump together into hair-like amyloid fibrils. These cause FAP by building up around peripheral nerve and muscle tissue, causing numbness, weakness, even failure of the gastrointestinal tract.

The current treatment for FAP is a liver transplant, which replaces the mutant gene with a normal copy.

A paper in Science dated Sept. 28, 2001, reports: ¿Trans-suppression of misfolding in an amyloid disease.¿ The improbably strategy tested by the co-authors, at the Scripps Research Institute in La Jolla, Calif., embodies a paradox: Faced with one mutant FAP gene, they introduced a second mutated gene, which prevented the aberrant shape changes.

Their rationale is to keep the tetramer from disassembling into fibril-forming monomers. In fact, they showed in E. coli that when this mutation in one allele of the TTR gene occurs alongside a different mutation in the second allele, a protein encoded by the latter could prevent protein misfolding and amyloid formation. That is, two mutants are better than one.

This approach, they propose, may form the basis for a new FAP therapy, consisting of an injection into a patient of the suppressor protein. Once gene therapy becomes practical, the suppressor gene could be inserted directly into the organ that makes the aberrant protein. It would be incorporated during biosynthesis, thus foiling later misfolding.

This game plan, the authors suggest, may be generally useful for intervening in other amyloid diseases.