Lineage trees for cells

Lineage trees for cells, Weizmann Institute scientists develop new analytical method

REHOVOT, ISRAEL, October 28, 2005 – Some fundamental outstanding questions in science – "Where do stem cells originate?" "How does cancer develop?" "When do cell types split off from each other in the embryo?" – might be answered if scientists had a way to map the history of the body's cells going back to the fertilized egg. Now, a multidisciplinary team at the Weizmann Institute of Science has developed an analytical method that can trace the lineage trees of cells.

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 in the genome are thought to be trivial and mainly irrelevant. But research students Dan Frumkin and Adam Wasserstrom of the Institute's Biological Chemistry Department, working under the guidance of Prof. Ehud Shapiro of the Biological Chemistry and Computer Science and Applied Mathematics Departments, raised a new possibility: though biologically insignificant, the accumulated mutations might hold a record of the history of cell divisions. These findings were published today in PLoS Computational Biology.

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 treated as information and used to trace lineage on a large scale, and then applied the theory to extracting data and drafting lineage trees for living cells.

Methods employed until now for charting cell lineage have relied on direct observation of developing embryos. This method worked well enough for the tiny, transparent worm, C. elegans, which has a total of about 1,000 cells, but for humans, with 100 trillion cells, or even newborn mice or human embryos at one month, each of which has one 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. In microsatellites, a genetic "phrase" consisting of a few nucleotides (genetic "letters") is repeated over and over; 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 mouse genomes contain around 1.5 million microsatellites, but the team's findings demonstrated 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 in order to place organisms on branches of the evolutionary tree, the researchers assembled 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 then outlines the cell lineage tree. To check their system, they pitted it against the tried-and-true method of observing cell divisions as they occurred in a lab-grown cell culture. The team found that, from an analysis of just 50 microsatellites, they could successfully recreate an accurate cell lineage tree.

While the research team plans to continue to test 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. Says Prof. Shapiro, who heads the project: "Our discovery may point the way to a future 'Human Cell Lineage Project' that would aim to resolve fundamental open questions in biology and medicine by reconstructing ever larger portions of the human cell lineage tree."

### Contact: Elizabeth McCrocklin EMcCrocklin@jgordonassociates.com 212-871-3020 American Committee for the Weizmann Institute of Science For additional information see www.weizmann.ac.il/udi/plos2005.

Prof. Ehud Shapiro's research is supported by the M.D. Moross Institute for Cancer Research, the Dolfi and Lola Ebner Center for Biomedical Research, the Samuel R. Dweck Foundation, the Benjamin and Seema Pulier Charitable Foundation, the Robert Rees Fund for Applied Research, Dr. Mordecai Roshwald, and the Estate of Klara (Haya) Seidman. Prof. Shapiro is the incumbent of the Harry Weinrebe Professorial Chair.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,500 scientists, students, technicians, and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials, and developing new strategies for protecting the environment.

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'Know Thyself' — Easier Said Than Done

Benjamin Franklin wrote in his 1750 Poor Richard's Almanac that "There are three things extremely hard: steel, a diamond, and to know one's self." The problem of achieving accurate self-knowledge hasn't gotten any easier in 250 years; and, as shown in a new research report, there are major real-world consequences to this very human attribute.

In "Flawed Self-Evaluation: Implications for Health, Education, and the Workplace," investigators David Dunning (Cornell), Chip Heath (Stanford), and Jerry M. Suls (University of Iowa) summarized current psychological research on the accuracy (or rather inaccuracy) of self-knowledge, across a wide range of studies in a range of spheres. Their report is published in the December 2004 issue of Psychological Science in the Public Interest, a journal of the American Psychological Society.

A consistent and sobering picture emerged from the team's analysis: On the job, at school, or even in managing our own health, it is as though we all live in Garrison Keillor's fictional Lake Wobegon, "where all the children are above average." People's opinions of themselves, their abilities, and their health outlooks are generally skewed quite strongly in a positive direction.

Such errors in self-assessment can have serious consequences, for example in how people manage their own health. People generally underestimate their own susceptibility to serious health risks like high blood pressure, cancer, or food poisoning — partly because they overestimate how different they are from the norm in terms of behaviors that might put them at risk. This can influence the steps people take — or don't take — to prevent or treat such problems. On the other side of the health equation, doctors (being people too) overestimate their competence to treat problems outside their areas of specialization.

A similar overconfidence is found in education at all levels. Students and people undergoing professional training show a strong tendency to overestimate their mastery of new knowledge and skills, and teachers and peers are generally much better able than a student is to accurately predict the student's performance on tests.

The work world is full of overconfidence and flawed self-knowledge as well. Employees underestimate how long they will take to complete tasks. And CEOs and entrepreneurs are famously (sometimes disastrously) overconfident in making business decisions, particular when venturing into unfamiliar territory such as a business startup or an acquisition — a problem the authors called "the problem of the new."

Although a degree of self-deception may be just part of human nature, individuals aren't completely to blame for their lack of accurate self-knowledge, according to Dunning. There are social and institutional barriers to self-knowledge, such as the difficulty of giving honest critical feedback in workplace settings, as well as to the simple fact that people don't have access to the full range of human competence and skill against which to evaluate their own. Also, in many areas, what people are striving for — excellence — is ill-defined.

News Release, October 28, 2005For Immediate Release Read the Report Contact: David Dunning dad6@cornell.edu Chip Heath chip.heath@stanford.edu Jerry Suls jerry-suls@uiowa.edu

Psychological Science in the Public Interest provides definitive assessments of topics where psychological science may have the potential to inform and improve the lives of individuals and the well-being of society. The American Psychological Society represents psychologists advocating science-based research in the public's interest. ###

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