Landmark Study Unlocks Stem Cell, DNA Secrets To Speed Therapies

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Landmark Study Unlocks Stem Cell, DNA Secrets To Speed Therapies

http://www.medicalnewstoday.com/articles/125228.php

In a groundbreaking study led by an eminent molecular biologist at

Florida State University, researchers have discovered that as

embryonic stem cells turn into different cell types, there are

dramatic corresponding changes to the order in which DNA is

replicated and reorganized.

The findings bridge a critical knowledge gap for stem cell

biologists, enabling them to better understand the enormously complex

process by which DNA is repackaged during differentiation - when

embryonic stem cells, jacks of all cellular trades, lose their

anything-goes attitude and become masters of specialized functions.

As a result, scientists now are one significant step closer to the

central goal of stem cell therapy, which is to successfully convert

adult tissue back to an embryo-like state so that it can be used to

regenerate or replace damaged tissue. Such therapies hold out hope of

treatments or cures for cancer, Parkinson's disease, multiple

sclerosis, spinal cord injuries and a host of other devastating

disorders.

Using mouse and human embryonic stem cells, FSU researchers employed

advanced imaging techniques and state-of-the-art genomics technology

to demonstrate, with unprecedented resolution along long stretches of

chromosomes, which sequences are replicated first, and which occur

later in the process of differentiation.

" Understanding how replication works during embryonic stem cell

differentiation gives us a molecular handle on how information is

packaged in different types of cells in manners characteristic to

each cell type, " said M. Gilbert, the study's principal

investigator. " That handle will help us reverse the process in order

to engineer different types of cells for use in disease therapies. "

Internationally renowned for his body of cutting-edge research on

chromosomal structure and reproduction that he began as a doctoral

student at Stanford University in the 1980's, Gilbert joined the FSU

faculty and was appointed as the first J. Herbert

Distinguished Professor of Molecular Biology in 2006.

Results from the FSU study, which includes contributions from

researchers at three other institutions, are described in a paper

published in PLoS Biology, a peer-reviewed journal that showcases

biological science research of exceptional significance. So

prodigious were the findings that the current paper - " Global

Reorganization of Replication Domains During Embryonic Stem Cell

Differentiation " - is focused solely on results observed in the mouse

embryonic stems cells; data on the human cells will be detailed in a

future report.

" We know that all the information (DNA) required to take on the

identity of any tissue type is present in every cell, because we

already can, albeit very inefficiently, create whole animals from

adult tissue through cloning, " Gilbert said. " We also can make a kind

of artificial embryonic stem cells, called induced pluripotent stem

cells, out of many adult cell types, but there are two major hurdles

remaining. First, the methods currently used rely on the unnatural

retroviral insertion of genes into patients' cells, and these genes

are capable of forming tumors. Second, this method is very

inefficient as well because only one in 1,000 cells into which the

genes are inserted becomes pluripotent. We must learn how cells lose

pluripotency in the first place so we can do a better job of

reversing the process without risks to patients.

" The challenge is, adult cells are highly specialized and over the

course of their family history over many generations they've made

decisions to be certain cell types rather than others, " he said. " In

doing so, they have tucked away the information they no longer need

on how to become other cell types. Hence, all cells contain the same

genetic information in their DNA, but during differentiation they

package it with proteins into 'chromatin' in characteristic ways that

define each cell type. The rules that determine how cells package DNA

are complicated and have been difficult for scientists to decipher. "

But, Gilbert noted, one time that the cell " shows its cards " is

during DNA replication.

" During this process, which was the focus of our FSU research, it's

not just the DNA that replicates, " he said. " All the packaging must

be replicated as well in each cell division cycle. "

He explained that embryonic stem cells have many more,

smaller " domains " of organization than differentiated cells, and it

is during differentiation that they consolidate information.

" In fact, 'domain consolidation' is what we call the novel concept we

discovered, " he said.

Gilbert likened the concept of domain consolidation to the undeclared

or " undifferentiated " college student who then consolidates her

literature resources during the course of declaring a major and

specialization. " From a student with books on all subjects on all of

her bookshelves comes a student who has placed all texts pertaining

to her major on the eye-level shelf and moved the distantly-related,

potentially distracting texts to the hard-to-reach bottom or top

shelves, " he said.

" Now, our challenge as scientists, " said Gilbert, " is to build on

what we've learned about domain consolidation so that we can

efficiently and safely create patient-specific induced pluripotent

stem cells or even coax the body's cells to change their

specialization in response to medications. "