Sounds useful to us. Who is going to translate this into a stroke protocol?
http://www.alphagalileo.org/ViewItem.aspx?ItemId=130405&CultureCode=en
In a serendipitous discovery, scientists at The Scripps Research
Institute (TSRI) have found a way to turn bone marrow stem cells
directly into brain cells.
Current techniques for turning patients’ marrow cells into cells of
some other desired type are relatively cumbersome, risky and effectively
confined to the lab dish. The new finding points to the possibility of
simpler and safer techniques. Cell therapies derived from patients’ own
cells are widely expected to be useful in treating spinal cord injuries,
strokes and other conditions throughout the body, with little or no
risk of immune rejection.
“These results highlight the potential of antibodies as versatile
manipulators of cellular functions,” said Richard A. Lerner, the Lita
Annenberg Hazen Professor of Immunochemistry and institute professor in
the Department of Cell and Molecular Biology at TSRI, and principal
investigator for the new study. “This is a far cry from the way
antibodies used to be thought of—as molecules that were selected simply
for binding and not function.”
The researchers discovered the method, reported in the online Early
Edition of the Proceedings of the National Academy of Sciences the week
of April 22, 2013, while looking for lab-grown antibodies that can
activate a growth-stimulating receptor on marrow cells. One antibody
turned out to activate the receptor in a way that induces marrow stem
cells—which normally develop into white blood cells—to become neural
progenitor cells, a type of almost-mature brain cell.
Nature’s Toolkit
Natural antibodies are large, Y-shaped proteins produced by immune
cells. Collectively, they are diverse enough to recognize about 100
billion distinct shapes on viruses, bacteria and other targets. Since
the 1980s, molecular biologists have known how to produce antibodies in
cell cultures in the laboratory. That has allowed them to start using
this vast, target-gripping toolkit to make scientific probes, as well as
diagnostics and therapies for cancer, arthritis, transplant rejection,
viral infections and other diseases.
In the late 1980s, Lerner and his TSRI colleagues helped invent the
first techniques for generating large “libraries” of distinct antibodies
and swiftly determining which of these could bind to a desired target.
The anti-inflammatory antibody Humira®, now one of the world’s
top-selling drugs, was discovered with the benefit of this technology.
Last year, in a study spearheaded by TSRI Research Associate Hongkai
Zhang, Lerner’s laboratory devised a new antibody-discovery technique—in
which antibodies are produced in mammalian cells along with receptors
or other target molecules of interest. The technique enables researchers
to determine rapidly not just which antibodies in a library bind to a
given receptor, for example, but also which ones activate the receptor
and thereby alter cell function.
Lab Dish in a Cell
For the new study, Lerner laboratory Research Associate Jia Xie and
colleagues modified the new technique so that antibody proteins produced
in a given cell are physically anchored to the cell’s outer membrane,
near its target receptors. “Confining an antibody’s activity to the cell
in which it is produced effectively allows us to use larger antibody
libraries and to screen these antibodies more quickly for a specific
activity,” said Xie. With the improved technique, scientists can sift
through a library of tens of millions of antibodies in a few days.
In an early test, Xie used the new method to screen for antibodies
that could activate the GCSF receptor, a growth-factor receptor found on
bone marrow cells and other cell types. GCSF-mimicking drugs were among
the first biotech bestsellers because of their ability to stimulate
white blood cell growth—which counteracts the marrow-suppressing side
effect of cancer chemotherapy.
The team soon isolated one antibody type or “clone” that could
activate the GCSF receptor and stimulate growth in test cells. The
researchers then tested an unanchored, soluble version of this antibody
on cultures of bone marrow stem cells from human volunteers. Whereas the
GCSF protein, as expected, stimulated such stem cells to proliferate
and start maturing towards adult white blood cells, the GCSF-mimicking
antibody had a markedly different effect.
“The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish,” remembered Xie.
To Lerner, the cells were reminiscent of neural progenitor
cells—which further tests for neural cell markers confirmed they were.
A New Direction
Changing cells of marrow lineage into cells of neural lineage—a
direct identity switch termed “transdifferentiation”—just by activating a
single receptor is a noteworthy achievement. Scientists do have methods
for turning marrow stem cells into other adult cell types, but these
methods typically require a radical and risky deprogramming of marrow
cells to an embryonic-like stem-cell state, followed by a complex series
of molecular nudges toward a given adult cell fate. Relatively few
laboratories have reported direct transdifferentiation techniques.
“As far as I know, no one has ever achieved transdifferentiation by
using a single protein—a protein that potentially could be used as a
therapeutic,” said Lerner.
Current cell-therapy methods typically assume that a patient’s cells
will be harvested, then reprogrammed and multiplied in a lab dish before
being re-introduced into the patient. In principle, according to
Lerner, an antibody such as the one they have discovered could be
injected directly into the bloodstream of a sick patient. From the
bloodstream it would find its way to the marrow, and, for example,
convert some marrow stem cells into neural progenitor cells. “Those
neural progenitors would infiltrate the brain, find areas of damage and
help repair them,” he said.
While the researchers still aren’t sure why the new antibody has such
an odd effect on the GCSF receptor, they suspect it binds the receptor
for longer than the natural GCSF protein can achieve, and this lengthier
interaction alters the receptor’s signaling pattern. Drug-development
researchers are increasingly recognizing that subtle differences in the
way a cell-surface receptor is bound and activated can result in very
different biological effects. That adds complexity to their task, but in
principle expands the scope of what they can achieve. “If you can use
the same receptor in different ways, then the potential of the genome is
bigger,” said Lerner.
In addition to Lerner and Xie, contributors to the study, “Autocrine
Signaling Based Selection of Combinatorial Antibodies That
Transdifferentiate Human Stem Cells,” were Hongkai Zhang of the Lerner
Laboratory, and Kyungmoo Yea of The Scripps Korea Antibody Institute,
Chuncheon-si, Korea.
Funding for the study was provided by The Scripps Korea Antibody Institute and Hongye Innovative Antibody Technologies (HIAT).
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