New Worlds: A family tree for cells

Weizmann Institute researchers have developed an analytical method to trace the lineage "trees" of cells.

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November 19, 2005 22:14
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The Human Genome Project mapped out man's genetic makeup, but a "Human Cell Lineage Project" is still needed to map the history of the body's cells back to the fertilized egg. Now Weizmann Institute researchers have developed an analytical method to trace the lineage "trees" of cells. The method could answer numerous fundamental questions in biology and medicine, such as where do stem cells originate, how does cancer develop, and when do cell types split off from each other in the embryo. This accomplishment started with a challenge to common wisdom, which says that every cell in an organism carries an exact duplicate of its genome. Although mistakes in copying, which are passed on to the next generation of cells as mutations, occur when cells divide, such tiny flaws are thought to be trivial. But research students Dan Frumkin and Adam Wasserstrom of the Rehovot Institute's biological chemistry department, working under the guidance of Prof. Ehud Shapiro, raised a new possibility: Though biologically insignificant, the accumulated mutations might hold a record of the history of cell divisions. Together with Prof. Uriel Feige of the computer science and applied mathematics department and research student Shai Kaplan, they proved that these mutations can be used to trace lineage on a large scale, and then applied the theory to extracting data and drafting lineage trees for living cells. Methods used until now for charting cell lineage trees have relied on direct observation of developing embryos. This technique worked well enough for the tiny transparent worm C. elegans, that has a maximum of 1,000 cells, but for humans with 100 trillion cells, or even newborn mice or human embryos at one month, each of which has a billion cells after some 40 rounds of cell division, the task would be impossible. The study focused on mutations in specific, mutation-prone areas of the genome known as microsatellites (genetic phrases consisting of a few nucleotides or genetic letters); mutations manifest themselves as additions or subtractions in length. Based on the current understanding of the mutation process in these segments, the scientists proved mathematically that microsatellites alone contain enough information to accurately plot the lineage tree for a one-billion-cell organism. Both human and murine genomes contain around 1.5 million microsatellites, but the team's findings showed that a useful analysis can be performed based on a much smaller number. To obtain a consistent mutation record, the team used organisms with a rare genetic defect found in plants and animals alike. While healthy cells have repair mechanisms to correct copying mistakes and prevent mutation, cells with the defect lack this ability, allowing mutations to accumulate relatively rapidly. Borrowing a computer algorithm used by evolutionary biologists that analyzes genetic information to place organisms on branches of the evolutionary tree, the researchers put together an automated system that samples the genetic material from a number of cells, compares it for specific mutations, applies the algorithm to assess degrees of relatedness, and from there outlines the cell lineage tree. To check their system, they pitted it against the tried-and-true method of observing cell divisions as they occur in a lab-grown culture. The team found that, from an analysis of just 50 microsatellites, they could recreate an accurate cell lineage tree. While the research team plans to continue testing their system on more complex organisms such as mice, several scientists have already expressed interest in integrating the method into ongoing research in their fields. THE STOMACH NEVER LIES Instead of looking at brain waves or sweaty palms, lie detector experts may be advised to focus on the stomach instead. A new study suggests that changes in gastric physiology perform better than standard polygraph methods in distinguishing between lying and telling the truth. The University of Texas study, presented at the recent Annual Scientific Meeting of the American College of Gastroenterology, demonstrates a link between lying and a significant increase in gastric arrhythmia. To test their hypothesis that the gastrointestinal tract is uniquely sensitive to mental stress because of the communication between the central nervous system and the enteric nervous system, University of Texas researchers recruited 16 healthy volunteers to undergo simultaneous electrogastrogram (EGG) and electrocardiogram (ECG) recordings. The researchers found that both lying and truth telling affected cardiac symptoms, while the act of lying was also associated with gastric symptoms. The EGG showed a significant decrease in the percentage of normal gastric slow waves when the subject was lying. That corresponded to a significant increase in the average heart rate. "We concluded that the addition of the EGG to standard polygraph methods has clear value in improving the accuracy of lie detectors," said Dr. Pankaj Pasricha, the chief researcher. "The communication between the big brain and the little brain in the stomach can be complex, and merits further study," he said. CELLPHONES & HOSPITALS GET ALONG Improved cellular phones and medical equipment appears to have lessened the phones' interference with hospital monitors and respirators, a Mayo Clinic study indicates. Researchers there reached this conclusion after spending four years studying the interaction between the two. Many hospitals ban the use of cellphones on the premises, or restrict them to certain areas. In their most recent analysis, Mayo Clinic researchers report in the the October issue of Mayo Clinic Proceedings that the cellphones they tested didn't interfere with medical devices more than a meter away, marking an improvement. Nearly half of the devices recorded some interference, but the vast majority of such interference should not have had any significance for the patient. The researchers completed their study of six models: Nokia Model 5165 (digital); Sanyo Model SCP-4900 (digital); Nokia Model 3585i (digital); Motorola Model 205 (digital); Motorola V60 (digital); and Nokia Model 3585i (analog). Dr. David Hayes, head of the cardiovascular disease division at the Mayo Clinic, said that since technological changes in both cellular phones and medical equipment continue, periodic testing of the communications devices to determine their effects on medical equipment will be needed.

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