Six
Scottish scientists have been given £13m to find a drug to treat three of
the world most unpleasant diseases. Sleeping sickness, leishmaniasis and
Chagas' disease are all caused by parasites spread by blood-sucking insects.
Between them they infect millions in Africa, Asia and Latin America. There
are no safe, reliable treatments, and, because the victims are almost invariably
poor, little interest from the pharmaceutical companies.¬Ý
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."
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.
