STEM CELLS AND CLONING: FACT AND FICTION - YOU BE THE JUDGE.  Part II of II

                                                        Dr. R. Rajaraman

Adult Stem Cells:
 Another kind of stem cells often called adult stem cells can be obtained
from different tissues  or organs  such as skin, brain, kidney, liver, bone
marrow, or blood.   This is because, even after the birth and growth of an
individual, a pool of resident 'adult' stem cells (are these the residual
original embryonic stem cells?) is maintained in many adult tissues.  The
adult stem cells can give rise to various cell types of that specific organ,
from which the stem cells have been obtained.  In some instances they have
been shown to undergo transdifferentiation into cell types of other tissues;
in other words, they can produce cells of a different tissue other than the
one from which the stem cells were isolated. (For example, a cell on the way
to become a bone cell may change is mind halfway and become a muscle cell,
provided if it receives the right signals.)  Thus, it is believed that
during the development of the embryo, the differentiation potential of
individual stem cells becomes progressively restricted, although there are
many exceptions to this belief.  Recently several laboratories have reported
tissue derived adult stem cells can transdifferentiate into a cell type of
another tissue.  However, adult stem cells have not been shown to exhibit
developmental potential matching the breadth and versatility equivalent to
that of the embryonic stem cells.

 A good example of adult stem cell-based regenerative medicine is the work
of  Dr. Michel Levesque, who uses the patient's own neural stem cells. He
removed neural stem cells from the patient's  brain, cultured them in the
lab for months to produce several million  stem cells and then implanted
them into the part of the brain that is affected by the lack of dopamine
producing cells. This  work holds tremendous promise for curing PD. Adult
stem cells have been used to cure several patients in France with an
inherited disease sickle cell anemia as well as reversal of multiple
sclerosis in Canada and China.   Adult stem cells have also been used to
induce remission in several cancer patients and in improving patient
conditions with stroke and rheumatoid arthritis

Somatic Cell Nuclear Transplant (SCNT) and Stem Cells from self-embryo:
             If one uses an embryo to obtain stem cells for regenerative
medicine, the chances are that the foreign stem cells will be rejected by
the recipient's immune system.  For this reason, it would be preferable to
use the patient's own stem cells for such therapeutic applications.  Apart
from the above mentioned adult stem cells, there are two ways one can obtain
stem cells from self.   One can artificially produce an embryo using the
patient's own cells (e.g., skin cell or a brain cell).  This is exactly what
is done in the above mentioned procedure called Somatic Cell Nucleus
Transplant or SCNT.  In this approach, one removes and discards the nucleus
from an unfertilized egg (this nucleus contains only one half or haploid
number of chromosomes coming from the female; therefore cannot by itself
develop into an embryo, except under very abnormal circumstances called
parthenogenesis, which produce only female individuals; so no embryo is
killed in this procedure) and introduces the diploid nucleus (complete
diploid number of chromosomes) from a somatic cell (e.g., a skin cell) of an
adult individual. The diploid nucleus begins to act like a fertilized egg in
the presence of all the required messages in the cytoplasm of the egg when
given the right microenvironment in vitro and develops into an embryo-like
collection of cells resembling a blastocyst stage.

 At this stage one can do one of two things:

             1. Reproductive cloning:  One can implant the embryo-like
artificial blastocyst produced without fertilization by SCNT into a
surrogate mother and can obtain a cloned identical duplicate of the
individual who donated the somatic cell nucleus.  As mentioned above, this
technology is not advanced enough to produce a healthy individual.
Experiments with cats did produce normal looking kittens, but they were not
identical among themselves and differed from their biological mother, for
unknown reasons.  Besides, there are other problems, such as a cloned
organism may carry unknown genetic and epigenetic defects, and tend to
retain the genetic age of the donor.  It is also morally and ethically wrong
to kill several hundred fetuses, before we obtain one successful clone, even
assuming that everything goes without a flaw.  Alternatively, some people
would prefer to terminate the surrogate conception after an advanced state
to isolate embryonic stem cells, which is morally and ethically even
inconceivable.

             2. "Therapeutic Stem cell Cloning" or "Therapeutic Cloning"
following somatic cell nuclear transfer (SCNT) is a procedure to culture the
embryo-like artificial blastocysts in vitro and isolate the embryonic stem
cells from them and culture them for solely for the purpose of therapeutic
research.  (I hate the phrase "Therapeutic Cloning", since it has taken a
wrong meaning causing furore and objections to this branch of developing
science; the stigma of cloning means human cloning has stuck in people's
mind.)  This is just a procedure to obtain patient's  own embryonic stem
cells, that can be used for regenerative medicine for that particular
patient alone.   The nucleus is the site of DNA, which contains the "blue
print" of life.  The DNA in the nucleus contains all the genes that code for
the development and differentiation of all of the more than 200 different
cell types and to organize them into a functional human being.  But, not all
the genes are coding for their respective protein in all the cells at a
given time.  For example, the skin cell nuclear DNA will be synthesizing the
proteins required for the skin cells, while all the other genes are kept in
an inactive state. The cytoplasm of the enucleated egg has the messages
necessary to instruct the somatic cell nucleus (from a skin cell for
example) to inactivate the battery of genes that are active in the skin cell
and turn on the battery of genes that would be active in the embryonic cell.
This is what happens when a somatic cell nucleus is transplanted into an
enucleated egg cell (oocyte), (which will not develop into an embryo by
itself since it has a haploid nucleus with only one half of the number of
chromosomes).  The diploid somatic cell nucleus acquires the gene expression
profile of an embryo, starts behaving like an embryo in vitro and by day 4-5
reaches the blastocyst stage, with its central mass of cells rich in
embryonic stem cells (instead of adult stem cells).  Thus, the therapeutic
stem cell cloning (or erroneously called therapeutic cloning) involves
harvesting of these cells from the artificial blastocysts and culturing them
in vitro for therapeutic research purposes.  It is hoped that such embryonic
stem cells will be pluripotent and may not be rejected by the patient .
However, the cytoplasm of the egg into which the somatic cell nucleus is
transplanted, will have the mitochondrial DNA from the egg.  So, what we
really have here is a human-human (egg cytoplasm/ somatic nucleus) hybrid
cell with the egg mitochondria (small respiratory organelles of the cell)
contributing about 1% of the total cellular DNA and the rest of the 99% of
DNA coming from the nucleus of the donor cell.  (Yes! We all get our
mitochondria  from our mothers!)  This may also be likely to cause immune
rejection of the patient's own stem cell!  As I see it, it is only a matter
of time this small obstacle will be surmounted.  One can carefully extract
the cytoplasm of the egg cell, remove the maternal mitochondria from the
cytoplasmic fluid and inject cytoplasmic fluid minus the mitochondria into
the somatic cell.  Alternatively, one can inactivate the maternal
mitochondrial DNA from the enucleated egg and inject the somatic nucleus
along with patient's own mitochondria.  Such a hybrid embryo will have 100%
of the DNA derived from the patient alone, thus avoiding the possibility of
immune rejection.  At present, there are only proofs of principle behind
this optimism. But these are strong indications that if we allow exploration
of  these new opportunities of developing novel regenerative therapies,
there shall be enormous benefits to be garnered.   However, these novel and
highly probable opportunities to develop regenerative medicine needs to be
validated by further research.  It only makes sense that "we are ethically
and morally obliged to pursue them for the benefit of those who suffer."

         Now, we know what the stem cell is capable of doing.  Given this
scenario, people with debilitating diseases, for which there are no cures
available in the foreseeable future, have put their faith on stem cell
research.  Forty American Nobel Laureates, that includes world authorities
in research on cancer and other life-threatening diseases, issued a joint
statement on April 10, 2002, strongly in favor of somatic cell nuclear
transplantation technology for therapeutic research.  Therapeutic stem cell
cloning means isolating the embryonic stem cells from the artificially
produced self-embryo and growing them in large numbers to be used in
therapeutic research and not for producing babies.  However, we all agree it
is ethically and morally repugnant to kill a human embryo to save another
human life.  The best compromise would be to take the patient's own cell and
make it think and act like an embryo.


"WHEN IS A CLONE NOT A CLONE?"
          People think it would be okay to isolate adult stem cells from
somatic tissues such as skin, bone marrow or blood. In theory, these cells
are also pluripotent and can be put in an egg for the purpose of cloning an
individual!  Therefore, no matter where you get the stem cells from, either
from an early embryo, an induced embryo after SCNT, or an adult tissue,
given the right environment, all are potentially capable of developing into
an embryo!  That is why they are called STEM Cells.

         As mentioned above, SCNT or Somatic Cell Nuclear Transfer can be
common for both reproductive cloning and therapeutic stem cell culture
(therapeutic cloning).  But there ends the similarity.   The moral or
ethical question, therefore,  is  "Do we have the right to kill a
 "potential" embryonic human being for culturing stem cells?"   This might
appear as a grey area.  Therefore, it is reasonable to assume that both the
pro-life and pro-stem cell sides have some grain of truth in their
respective contentions.  But, in practice, therapeutic stem cell culture is
different from cloning of one self, since we are not cloning babies.  This
is where one's common sense, judgement based on experience and society,
compassion, sensitivity, and cost benefit and ratio in terms of human
suffering come into play and one has to come to an appropriate decision
without approaching the issue with a one track mind and without being
hypocritical.

          When does a life begin?  It is correct to assume a life starts
immediately after the haploid nucleus of the sperm fuses with the haploid
nucleus of the egg, a process called fertilization.  If you are with me on
this definition, let us see what happens when people take birth control
pills.  Birth control pills induce a processes similar to abortion in that
they prevent implantation of fertilized eggs month after month almost
through out the reproductive life of the females of human species.  Except
the Catholic Church and probably a few staunch religious people, the vast
majority of the humanity does not feel guilty about millions or billions of
these potential human beings being "murdered" every day.  But, why should we
feel morally and ethically guilty if an ailing patient with no other way of
leading an useful life, for no mistake of his/her own wants to raise his/her
own stem cells using his/her own somatic cell to cure his/her disease?  If
we are truly pro-life, this should also encompass a normal healthy life
style for every human being, especially the ones that are alive but
suffering from various debilitating diseases.  I find this moral dilemma is
based essentially on ignorance of the understanding of the value of purpose
and the procedures involved. They not only propose to ban any research on
stem cells, but they also want to criminalize the act of doing research and
if the patient gets stem cell treatment outside America, he/she also would
be treated as criminal!  (This tendency has already resulted in the loss of
brain drain from both USA and UK to other parts of the world which embrace
these novel approaches!)  I smell lack of compassion, self-righteousness and
a streak of savage delight in imposing one's biased belief on others.

             North America is a pluralistic society and there are opposing
opinions in every society.  At the outset, there appears to be strong
opinion on both sides of the argument.  Proponents of banning embryonic stem
research however assume that adult stem cells will cure everything and so we
need to ban all embryonic stem cell research including SCNT-derived
therapeutic stem cell cultures or therapeutic cloning.  Yet, every
scientific review of the therapeutic opportunities afforded by adult and
embryonic stem cells has concluded that embryonic stem cells are far more
versatile for regenerative medical therapies.  It is too early to assume
that  adult stem cells will be as good as the embryonic stem cells in their
longevity and function.   Research on human stem cells have only started
very recently and is still in its infancy.   It makes a lot of sense to me
that research with both adult and SCNT-embryonic stem cells should be
allowed to proceed very vigorously without any further delay.  Time will
tell which would be the best approach to adhere to.  As Dr. Paul Berg puts
it, choosing one against the other at this point in time could prove to be
an erroneous choice of embarrassment, not unlike the experience of the
Soviets who preferred Lysenko's prejudices against Mendelian genetics.  It i
s gratifying to note that, in addition to the 40 Nobel Laureates, several
knowledgeable and influential people such as Senator Orrin G. Hatch, Nancy
Regan, Christopher Reeves, (including some pro-life people) and several
organizations including the American Medical Association, the American
Pediatric Association, the American Association of Medical Colleges,
American Society for Cell Biology, National Institutes of Health and many
patient advocacy organizations including Juvenile Diabetes Research
Foundation, the National Coalition for Cancer Survivorship, the Huntsman
Cancer Institute and the Utah Life Sciences Association favor encouraging
Somatic Cell Nuclear Transplantation for cloning stem cells for therapeutic
research.


             Does this mean no research on embryonic stem cells should be
allowed take place?  I think that is not the right decision at this time.
While reproductive cloning of humans be banned and criminalized permanently
along with severe punishments attached to such activities, I also think that
reproductive cloning of other organisms, safeguarded with strict ethical
guide lines, has an important role and purpose in propagating the animals
and plants that are facing extinction.  Humans as a species have come to
dominate by their successful colonization of the earth and are
indiscriminately destroying the natural environment that supported the
evolution of God's creation and because of this success or other reasons
thereof, several plant and animal species are already extinct or more are
lingering  at the verge of extinction.  For that purpose alone, we owe it to
ourselves and to our future generations, if not for anything else, we should
not hesitate to do all we can to preserve and cherish all life forms.
Studies on reproductive cloning can go a long way in achieving the
preservation of various life forms from becoming extinct.  One has only to
look at the popularity of science fiction movies such as "Jurassic Park!"
Wouldn't you be thrilled to produce a couple of baby mastadons or saber
tooth tigers by injecting the nuclei from the somatic cells of a deep-frozen
mastadon or a saber tooth tiger in the arctic into the enucleated eggs of an
elephant or a present day tiger?  By the way, even the present day elephants
and tigers are at the verge of extinction because of irresponsible hunting
by humans for fun or for profit!

 CONCLUSIONS:
             The words "stem cells" and "cloning" create intense and violent
emotional reactions in people  on both sides of the abortion issue.  The
fact is that stem cells are in our own blood, pancreas, liver, brain and
perhaps many other tissues and organs of the body.  These are adult stem
cells which have already begun marching on the differentiation pathways at
least partially into the kind of cells they are getting programmed to become
eventually.  It is thought that further research on adult stem cells as well
as stem cell derived after SCNT may play a major role finding cures for
various pathological conditions. Although some preliminary work looks
promising, one needs to verify the validity of these expectations by further
research before arriving at safe therapeutic protocols.  There are also stem
cells to be harvested from the placenta and the umbilical cord blood, which
is routinely discarded after the baby is born.  Cord blood cell banks are
being set up to help doctors and families donate their stem cells for
research and future therapy. The very mention of the words "Stem Cells" or
"cloning" makes people think about human cloning and they immediately accuse
the scientists of wanting to play God!  They forget that there are many
kinds of stem cells whose potential need to be understood better.  How do
they multiply without undergoing differentiation? What are the different
signals and the sequence of the events that lead to different cell types in
the body?  How are these signals being regulated? The stem cells are there
for the benefit of our well being. Why not exploit them for curing our
diseases?


             "Embryonic stem cells are another flash point of controversy.
These must be harvested from human embryos which are aborted.  We cannot
reconcile with taking a human life for prolonging another human life.  There
are serious trains of thought being argued about the use of "leftover"
embryos that are created by a couple using in vitro fertilization and which
are routinely destroyed by clinics and hospital every day.  It is at this
point the clouds of doubt and uncertainty rolls in:  What is more pro-life?
To allow the destruction of human embryos continue, which will never become
babies since they will never be transplanted into an woman's womb? Or is it
more pro-life to use these discarded (murdered) embryos to start new stem
cell lines for research thus giving them meaning and dignity to be useful
for humanity?"  You be the judge.  I have explained the choices presented by
the recent advances in science.  "I have to admit to not knowing answers to
this thorny and moralistic 'hot potato.' But I can tell you that years of
watching such debilitating diseases take our friends away all around us,
slowly but surely, sometimes makes us question the validity of our own
beliefs."

             So, back to the present again!  What is therapeutic stem cell
cloning?  There is a world of difference between reproductive cloning of
humans - something which should be banned universally and immediately, and
therapeutic stem cell cloning, that opens up unlimited opportunities to
benefit 75% of humanity by leading to cures for deadly and terrible
diseases.  Therapeutic stem cell cloning saves lives and make life worth
living; it does not create lives.  I hope I have helped somewhat in clearing
up some of the misconceptions and rekindled some hope that the pro-life and
the pro-choice people can find a common ground to come together in an
unified effort to eradicate the devastation and suffering of so many.  I
feel confident that after assimilating the facts,  the general public as
well as the politicians will make the right decisions in favor of the well
being of humanity.  But we cannot waste our time arguing about it.  We have
a lot of work to do and in a hurry!

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