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8-Humans: Gene defects plague stem-cell lines

------------------------------- GENET-news -------------------------------

TITLE:  Gene defects plague stem-cell lines
SOURCE: Nature, UK, by Roxanne Khamsi
DATE:   5 Sep 2005

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Gene defects plague stem-cell lines
Cancerous mutations threaten therapeutic future for cells.

Embryonic stem cells that are cultured in the lab accumulate an alarming
array of genetic changes, including mutations known to be linked to
cancer. The finding throws into question whether such cells could
eventually be used for therapy, unless they can be kept fresh and checked
for mutations before use.

Researchers think that stem cells, which can be programmed to grow into
any kind of cell, could one day be used to regenerate or replace cells
and organs damaged by disease. But growing these cells has proven problematic.

In January, researchers announced that most human embryonic stem-cell
lines, including ones approved by the US government for use in federally
funded studies, have been contaminated by animal cells used as a growth
medium in lab dishes. Any cell containing such foreign proteins would
presumably trigger a damaging immune response if transplanted into a
human patient. Researchers realized they would have to grow their cells
differently in order to use them for therapy.

Now another difficulty has come to light. The longer the cells are kept,
and the more they divide, the more errors they build up in their genetic
code. "These mutations we are finding are a much bigger problem," says
Aravinda Chakravarti of the Johns Hopkins University in Baltimore, Maryland.

Next generations

All DNA tends to accumulate mutations as it divides, because each step in
the copying process can introduce errors. But previous, smaller studies
of stem cells had not found problematic levels of mutations.

Chakravarti and his colleagues decided to take a closer look, examining
nine of the human embryonic stem-cell lines that have federal approval.
They compared frozen, archived cells with 'daughter' generations that had
been created from these.

Many of the archived cells seemed normal, although some had already
divided tens of times to build up cell numbers into the billions. But
errors began to appear after further divisions. Out of nine cell lines,
eight developed one or more genetic changes commonly observed in human
cancers, the team reports in Nature Genetics1.

Changing state of play

The finding undermines a general assumption that stem cells remain
unblemished until they are programmed to become a certain type of cell.
"This is not good news. It suggests that the biological properties of the
cells before and after replicating could be different," says Chakravarti.

It remains unclear what would happen if these stem cells were
transplanted into a patient. But Chakravarti thinks the results should
encourage the use of fresher stem cells or, preferably, genetic screens
of stem-cell lines before they are used for therapy.

Stem-cell expert Roger Pedersen of the University of Cambridge, UK, says
he takes a "glass half full" view of the findings, because the billions
of archived cells seemed normal. This shows that the replications needed
to boost stem-cell numbers to usable levels do not necessarily cause problems.

Pedersen adds that the study supports the idea that more, fresh stem-cell
lines would be useful for the scientific community: US federal research
currently relies on a very limited number of lines.


1 	Maitra A., et al. Nature Genet.Published onlie, doi: 10.1038/ng1631 (2005).


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