(My mouth is watering for these brains to be able to have the wherewithal
possible to go further and faster with this research!  This is why it is so
important for us to be active advocates!)

  ++++

The following year end review of the stem cell and SCNT research fields
appears in the December 30 issue of The Economists.

 

New work shows the promise, and pitfalls, of embryonic-stem-cell research

 

FOR believers, Christmas is a celebration of the virgin birth. This season,
however, researchers are pondering another sort of immaculate conception.
Somatic nuclear transfer, or "cloning" as it is more popularly known, is a
way of creating embryos without the conventional meeting of egg and sperm
that is needed to provide a full complement of the genetic material to make
a new individual. Embryos can also be created by parthenogenesis―a nifty
biological trick in which an unfertilized egg cell is coaxed into providing
all the genetic material required for embryonic development. In the January
issue of Wired, a popular technology magazine, researchers at Advanced Cell
Technology, an American biotechnology company, are reported to have used
both techniques to create human embryos healthy enough to make it through at
least the earliest stages of development.

 

Parthenogenesis occurs in the animal world. Many species of fish, birds and
snakes reproduce naturally through parthenogenesis. And cloning has been
performed in a wide variety of species, Dolly the sheep being its most
famous offspring. Many researchers would like to apply these techniques to
people.

 

 

Their interest is not procreation. Human reproductive cloning is so fraught
with technical risks and ethical dilemmas that few respectable scientists
will touch it, and parthenogenesis, while occasionally also observed in
mammals, never produces viable offspring. But if such embryos could be
coaxed far enough along the track of development to form multicellular
structures known as blastocysts, they could prove a useful source of stem
cells. Unlike most of the body's cells, which are locked into a single job
for life, embryonic stem cells are able to reproduce themselves repeatedly,
and when given the right biological signals, can mature into a wide range of
different cell types. This makes them a potential source of new cells to
repair damaged tissue in, say, diabetes or Parkinson's disease.

 

Michael West, Advanced Cell Technology's chief executive, is reluctant to
confirm Wired's story, which claims that the firm has managed to coax one of
its cloned embryos into a 16-cell entity called a morula―the predecessor of
a blastocyst. But Dr West does say that his firm has managed to generate
stem cells through parthenogenesis, and is working towards building a bank
of stem cells with particular immunological features, so that patients might
one day be treated using those that pose the lowest risk of graft rejection.

 

As Advanced Cell Technology has yet to publish the current research in a
peer-reviewed journal, and the firm is known to be searching for funds, many
experts are skeptical of its claims. Among the critics is Gerald Schatten, a
researcher at the University of Pittsburgh who is working on generating
embryonic stem cells from cloned monkey embryos. Primates (humans included)
are tougher to clone than other animals, he says, because the molecular
machinery needed for cell division is somehow impaired during the process of
cloning. Though Advanced Cell Technology may have managed to create
early-stage embryos, Dr Schatten awaits experimental evidence that these can
develop far enough for stem cells to be derived from them and that those
stem cells will, in turn, develop normally in a test tube.

 

Parthenogenesis, on the other hand, is proving a reliable source of
embryonic stem cells, at least in monkeys. Jose Cibelli, who once worked at
Advanced Cell Technology and is now a researcher at Michigan State
University, has managed to coax parthenogenetically derived embryonic stem
cells into forming various cell types, including nerve cells that produce
dopamine, a brain chemical whose deficiency leads to Parkinson's disease.
The next step is to inject these dopamine-producing cells back into monkeys
to see if they can do the same job inside a warm body.

 

An embryonic science

While research is yielding novel sources of embryonic stem cells, and ways
to give ordinary cells stem-like powers, it is also revealing new challenges
in translating this research from the laboratory bench to the patient's
bedside. One problem has to do with the way human embryonic stem cells are
cultivated in a test tube. Stem cells are hard to grow in sufficient
quantity and purity for research, let alone for therapeutic applications.
They dislike solitude and refuse to thrive unless they are in contact with
so-called "feeder" cells. These provide biochemical signals that allow stem
cells to maintain their unique characteristics and prevent them from
differentiating into mature cell types.

 

Mouse cells are normally used as feeders for human embryonic stem cells, but
many researchers are worried about employing differentiated cells derived
from such lines as actual human therapies, for fear they may have picked up
nasty viruses from their mouse feeders. Indeed, a recent report from a team
of stem-cell experts co-ordinated by Johns Hopkins University, in Baltimore,
has concluded that "it would be unethical to expose human subjects to
stem-cell lines that have been derived with mouse feeder layers."

 

A number of groups are working on alternatives. One possibility is to use
human, rather than mouse, feeder cells. Ariff Bongso, a stem-cell researcher
at the National University of Singapore, has tested a number of human cell
types and found that adult skin cells work just as well as mouse feeders at
keeping human embryonic cells healthy and happy.

 

Another option is to dispense with feeder cells altogether. In the January
issue of Nature Medicine, Ali Brivanlou and his team of researchers at
Rockefeller University in New York, the University of Athens in Greece and
the Centre National de la Recherche Scientifique in Roscoff, France, have
found a way of cultivating human embryonic stem cells for several
generations in the absence of feeder cells. Instead, they grow their cells
with a molecule called 6-bromoindirubin-3'-oxime (more catchily known as
BIO).

 

BIO is known to inhibit the activity of a molecule that acts as a brake on a
system of molecular signals called the Wnt pathway. Growing human embryonic
stem cells in the presence of BIO allows the Wnt pathway to function fully.
That, in turn, keeps the cells dividing without differentiating into other
cell types. Yet when exposed to the right environment, BIO-treated stem
cells still mature into special types, such as nerve cells, as efficiently
as those grown in more conventional conditions. Dr Brivanlou and his
colleagues are now trying to develop better molecules than BIO, in the hope
of using them to gain even more effective control over the process of
differentiation.

 

Lines in the sand

Despite these promising new approaches, many hurdles lie in the immediate
path of human embryonic stem cells. One is regulatory. On August 9th 2001,
President George Bush announced that federal funding for
human-embryonic-stem-cell research would be restricted to work done on those
cell lines established by that date. At the time, more than 60 such lines
from laboratories around the world were provisionally eligible. Today,
however, only a dozen or so lines are actually available for federally
funded researchers in America, since these are the only ones that laboratory
tests have so far proved have all the properties of bona fide human
embryonic stem cells.

 

This is a far cry from the rich pickings which such researchers were first
promised, and even this slender selection of eligible cells may not be so
desirable after all. It turns out that all the approved lines were grown
using mouse feeder cells. Yet scientists risk their federal grants if they
try to derive embryonic stem cells using alternative methods.

 

Another challenge has to do with the long-term behavior of human embryonic
stem cells―no matter their provenance―both in the test tube and in the human
body. In the January issue of Nature Biotechnology, Peter Andrews of the
University of Sheffield, in England, James Thomson of the University of
Wisconsin, and their colleagues, report that human-embryonic-stem-cell lines
grown over several months in the laboratory can develop genetic
abnormalities. In particular, the embryonic cells they studied gained extra
bits of chromosomes 12 or 17, which the group speculates may help these
cells retain their ability to renew themselves. But the researchers also
note that similar chromosomal changes are found in some types of cancer
cell, yet another concern when it comes to moving into the clinic.

 

How specialized cells derived from embryonic stem cells will behave in the
human body is a further uncertainty. As the Johns Hopkins report points out,
whether grafts of these fruits of embryonic stem cells will settle down in
the right place in the body, and keep doing their intended job rather than
becoming other cell types or, even worse, cancer cells, is unknown.

 

But results from animal experiments demonstrate their tantalizing potential.
In the December issue of Laboratory Investigation, Joseph Itskovitz-Eldor
and his team at the Technion-Israel Institute of Technology in Haifa show
how human embryonic stem cells can be coaxed (in a test tube) into becoming
the various cell types that make up blood vessels. Indeed, subsequent
experiments have demonstrated that, when injected into special experimental
mice, these differentiated cells are able to form fully functional blood
vessels which join up with the animal's own circulatory system. This is a
potential treatment for such things as ischemic heart disease.

 

But that path is littered with more than just technical obstacles. Embryonic
stem cells raise profound questions about the morality of using existing
embryos, or creating new ones, for the purposes of research on a medical
treatment, no matter how great the benefit. As the scientific barriers to
embryonic-stem-cell therapy fall, those ethical debates are set to deepen.

 

Nina

 

"Circumstances determine our lives, but we shape our lives by what we make
of our circumstances."

 


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