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Why are embryonic stem cells important?

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    Why are embryonic stem cells important?


    Wise Young, Ph.D., M.D.
    W. M. Keck Center for Collaborative Neuroscience

    Opponents of embryonic stem cell research often argue that embryonic stem cell research is not necessary because adult stem cells from bone marrow or umbilical cord blood cells are already curing diseases, are more likely to cure diseases, and that adult stem cells would not be rejected by the immune system when transplanted. They are troubled by the cloning because they oppose creating an embryo in order to harvest its stem cells. Finally, they point out that current methods of collecting embryonic stem cells are inefficient and cloning embryonic stem cells may not be a practical method of producing cells for transplantation purposes. These arguments are partly true but are misleading and do not justify the current restrictions of human embryonic stem cell research. Let us consider some of the most frequently cited arguments for or against adult and embryonic stem cells.

    1. Are adult stem cells already curing diseases? Some opponents of embryonic stem cell research say that embryonic stem cells have never cured any condition while adult stem cells are already curing many diseases. Bone marrow and umbilical cord blood stem cells have been used for over two decades to treat blood-making (hematopoietic cells) disorders, such as sickle cell anemia, thalassemia, radiation or chemotherapy induced bone marrow damage, and autoimmune diseases. Bone marrow stem cell transplants may accelerate and improve healing from heart attacks (myocardial infarcts) or failing hearts (congestive heart failure). However, there is no credible evidence yet that bone marrow stem cells are replacing heart cells. Bone marrow cells may be releasing factors that help hearts heal faster. Neither bone marrow nor umbilical cord blood stem cells, or other types of adult stem cells, have cured neurological conditions, such as brain or spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, or non-neurological diseases such as diabetes, liver damage from hepatitis, and other currently incurable conditions. We do not know enough now to predict whether adult or embryonic stem cells would be better or which would be more effective.. Many animal studies have shown beneficial effects of embryonic stem cell treatments of animal models of diseases. Human embryonic stem cells have not yet been transplanted into humans. There are no restrictions on adult bone marrow or umbilical cord blood research at all while U.S. federal government signficantly restricts funding of human embryonic stem cell research.

    2. Do adult stem cells circumvent the problem of immune rejection? It is true that autologous grafts, i.e. adult stem cells taken from a person and transplanted into the same person, would not be rejected by the immune system. However, autologous grafts cannot be used for many conditions. First, autologous grafts are not useful for most genetic diseases. For example, there is no point in taking bone marrow from a person with a genetic disease such as sickle cell anemia or thalassemia and then transplanting these cells back into the same person. Heterologous grafts, i.e. transplant from one person to another, are necessary. Second, autologous bone marrow grafts cannot be used to treat many autoimmune diseases, such as multiple sclerosis, diabetes, lupus erythematosus, scleroderma, etc. The transplanted bone marrow will produce cells with the same autoimmune tendencies. Third, bone marrow transplants often cause graft-versus-host disease where the transplanted cells regard the host body as "foreign" and attack it. As much as 50% of heterologous bone marrow transplants cause graft-versus-host disease with a high mortality rate. Fourth, even closely matched heterologous bone marrow transplants require immunosuppression. Destroying the bone marrow usually does this. Finally, umbilical cord blood does not produce as much immune response or as severe graft-versus-host disease. Human embryonic stem cells, because they are immature, are even less immunogenic and do not produce graft-versus-host disease.

    3. Are adult stem cells safer than embryonic stem cells for treatment of neurological disorders? Autologous transplants are very attractive for treating non-genetic diseases. For example, they would be an ideal treatment for traumatic brain and spinal cord injury, Parkinson's disease, stroke, and non-genetic conditions. However, heterologous transplants may be required for genetic conditions such Alzheimer's disease or amyotrophic lateral sclerosis. Even when bone marrow cells are carefully matched for histocompatibility, prolonged immune suppression may be required for engraftment. If selected stem cells are transplanted, particularly into brain or spinal cord, graft-vs. host disease would be unlikely. On the other hand, bone marrow transplants have a high complication rate, with a 20-50% incidence of graft-versus-host disease and 20-30% mortality rates. For these reasons, heterologous bone marrow transplants are seldom carried out except for life-threatening conditions. In contrast, embryonic stem cell transplants may not require as much or as prolonged immunosuppression because they do not express as many immunogenic proteins. Cloned embryonic stem cells that are genetically matched for the person should pose even less immunogenic risk.

    4. Do embryonic stem cells cause tumors? There are some claims that embryonic stem cells are more likely to cause tumors. All cells have the potential to cause tumors, particularly if they are grown for long periods in culture. Prolonged culturing increases the risk of malignant transformation of the cells. Immaturity of cells also may increase the likelihood of tumor formation. Some stem cells will not respond to all tissue factors and may produce the wrong type of cells, too many cells, or cells that transgress tissue boundaries. Cells with any of these three behaviors would be called a tumor. Because embryonic stem cells are often grown for long periods of time in culture, they have more of an opportunity to undergo malignant transformation. Because embryonic stem cells are immature compared to adult stem cells, they may not possess receptors to all tissue factors. However, much evidence now suggests that embryonic stem cells can be matured and pre-differentiated in culture before transplantation and that such cells are unlikely to produce tumors. This is a risk but not an insurmountable risk.

    5. Are adult stem cells more likely to result in cures for diseases than embryonic stem cells? Adult bone marrow or umbilical cord blood stem cells have been used to treat hematopoietic disorders for over 20 years. As pointed out above, heterologous bone marrow grafts may cause serious complications and are currently only used under the most dire circumstances. Umbilical cord blood transfusions show promise and presents less risk but appear to be less effective. Although some scientists have claimed that bone marrow mesenchymal stem cells can be induced to produce neurons and other cells under certain circumstances, their ability to do so is limited and substantial manipulation of the cells is required. In contrast, embryonic stem cells readily produce all types of cells, including neurons, insulin-producing cells, muscle, skin, and heart cells, both in culture and after transplantation. Embryonic stem cells also grow faster in culture and can be easily modified to produce specific cells with specific functions. We are perhaps expecting too much from adult stem cells when we transplant them into different tissues and expect them to fix disparate problems such as replacing insulin-producing cells, promote regeneration, remyelinate axons, repair heart tissues, and restore function to diverse organs. From this perspective, embryonic stem cells possess a significant advantage over adult stem cells. Because they grow indefinitely in culture, they can be produced in large numbers and be optimized to have more predictable and beneficial behavior after transplantation. At the present, we don't know which is more likely to result in cures for diseases.

    6. Is cloning necessary for embryonic stem cells to be used for transplantation? In biology, cloning means simply to produce cells with the same genes. Cellular cloning unfortunately has been associated with "reproductive cloning" or production of an individual with the same genes. One method of cloning embryonic stem cells is to transfer a nucleus into an egg and then trick the egg into producing stem cells. Called somatic cell nuclear transfer (SCNT), this method produces stem cells that have the same genes as the transferred nucleus. This method of cloning stem cells is currently inefficient, requiring dozens of eggs. In my opinion, cloning is not necessary for embryonic stem cells to be used for therapy. Doctors have successfully transplanted cells (blood) and organs (kidney, heart, liver, pancreas) for many decades without cloning. If the stem cells are carefully matched for histocompatibility genes (HLA) and immunosuppressive therapies are used, the cells will engraft. It is also possible to develop embryonic stem cell lines that express a limited set of histocompatibility antigens that would match 90% of people. Finally, immune rejection is not necessarily bad. The immune system eliminates cancer or excess cells. We may want the immune system to eliminate the cells after they have finished their work. In any case, much work needs to be done on cloning before it can be used clinically. For example, I don't think that it would be harmful to have 3-year moratorium on cloning of human embryonic stem cells but allow animal and human embryonic stem cell research to go forward. On the other hand, a ban of SCNT would be a serious mistake because it is a general technique that is important for many other clinical applications.

    7. Are embryonic stem cells practical? At the present, we do not have enough cells from any source that can be used to treat millions of people. For example, the world supply of umbilical cord blood is about 200,000 units. This is barely sufficient to satisfy the needs of 12,000 pediatric patients who need umbilical cord stem cells every year to treat their hematopoietic disorders. Although many laboratories have been trying for decades to grow stem cells from bone marrow, umbilical cord, placental, and other postnatal sources of stem cells, no reliable method is available to produce sufficient diversity and amounts of bone marrow or umbilical cord stem cells to treat millions of people. If any stem cell turned out to be useful for any of the major diseases, we do not have enough cells to treat even a tiny fraction of the people. Because they grow indefinitely in culture, embryonic stem cells provide a possible inexhaustible supply of stem cells that can treat millions of people. A cell bank with several thousand lines of human embryonic stem cells, for example, would be very helpful to satisfy current therapeutic and research needs.

    8. What other ways can human embryonic stem cells help cure diseases? Opponents of embryonic stem cell research seldom mention one important use of human embryonic stem cells. An embryonic stem cell line derived from a person with a genetic disease would be a very powerful tool to study that genetic disease. For example, if we had an embryonic stem cell lines from somebody with Alzheimer's, amyotrophic lateral sclerosis, Huntington's disease, diabetes, rheumatic arthritis, lupus erythematosus, etc. the cells can be used to assess mechanisms and treatments. At the present, we have to use animal models or human cadaver materials. Availability of human embryonic stem cell lines will allow large-scale screening of drugs and other treatments. Finally, many parents who use in vitro fertilization methods may have specific genetic conditions causing infertility. Eggs from infertility clinics may provide insight into genetic causes of infertility. Last but not least, the availability of such human disease-specific stem cell lines should reduce use of animals for studying human disease.

    In summary, adult bone marrow and umbilical cord blood stem cells have long been used to treat hematopoietic disorders. Obtaining stem cells from one part of the body and transplanting to another would circumvent immune rejection but most genetic diseases cannot be treated with such transplants. Bone marrow grafts tend to be immunogenic and cause graft-versus-host disease where transplanted immune cells attack the host. Human umbilical cord blood transplants are less immunogenic and cause less serious graft-versus-host disease. Human embryonic stem cells are even less immunogenic and do not cause graft-versus host disease. Stem cells may produce tumors after transplantation if they do not respond to all tissue factors, produce the wrong type or numbers of cells that do not respect tissue boundaries. All cells have some potential for malignant transformation. Differentiating stem cells in culture before transplantation reduces the risk of tumors. Cloning should produce genetically matched stem cells but we have much work to do before cloning can be applied clinically. Doctors have been transplanting cells and organs for many years without cloning. Embryonic stem cell research should go forward, even without cloning. We do not now have an adequate stem cell supply to treat even a small fraction of people who may benefit from stem cell therapies. Embryonic stem cells can be grown indefinitely to treat millions of people. Human embryonic stem cell lines obtained from people with specific genetic diseases will greatly accelerate research on many genetic diseases, including infertility, and will reduce the use of animals. Thus, it is important not to close the door on human embryonic stem cell research.

    Dr. Young,
    Maybe I am misunderstanding what you said...I think you said a temporary ban on SCNT/therapeutic cloning would be okay in your opinion? A moratorium or suspension for a period of time is equal to a ban.
    All of the researchers trying to cure SCI or other diseases using this method would have their research stopped in it's tracks. What a huge waste. A waste of money donated for the research, a waste of time spent, a waste of lives. Researchers would have to start over. In my opinion, the people suffering and dieing who might benefit from this in the future can't and shouldn't have to wait for a 3 year or whatever time period for the research to resume progressing toward what might be help for them in their lifetime when it can be ethically done and regulated.


      Dr. Young,

      If I may make a suggestion, I have been speaking to a number of influential people who support Brownback's bill. In speaking with them, they accept the fact that ESCs offer a great deal of potential. The issue that they oppose is not research on embryonic stem cells, but the destruction of the blastocysts required to extract the stem cells.

      I believe a more effective way of talking about this issue would be to focus on the fact that embryonic stem cells can be obtained without creating a new life [ie, cloning] only to prevent it from having a shot at life by extracting the inner cell mass from the blastocyst. Maybe a member who is Catholic can validate this for me, but I believe Catholics are against germ line modification. If true, enucleating an egg cell would also be a stumbling bock for them.

      You have said yourself that ESC and SCNT should be treated as separate arguments and have cautioned against unnecessarily tying the two together.

      In summary, focus on non-destructive ways to obtain embryonic stem cells. The debate is primarily over cloning, not whether or not ESC research is useful.

      With that in mind, would you be able to do a "Why is SCNT important?" write-up?


      -Steven a diamond, in the rough's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.


        Hope, are you assuming that *only* cloned embryonic stem cells can be transplanted? In the three years, a lot of work can be done to make cloning of stem cells (i.e. having stem cells with the same genes as the recipient) a practical procedure for clinical application. It will take three years to ensure that it can be done on a scale where it can be applied to clinical trial.

        Steven, the House of Representatives has actually separated the two. There will be two bills that people will be voting on... one on allowing use of IVF embryos that will be discarded and the other on SCNT. I oppose a general ban of SCNT.

        I don't see the piont of removing a single cell from a blastocyst that would be thrown away anyway. By the way, embryos cannot be thawed and frozen without damaging them.



          Thanks for the response, Wise.

          Would you support a more specific bill to ban certain uses of SCNT? If so, which uses would you consider okay to ban?

 a diamond, in the rough
's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.


            Steven, how about a bill that bans the implantation of a non-fertilized human egg into a woman's uterus? This is essentially the British bill which stops any possibility of further development of a cloned embryo into a viable fetus.

            Hope, one additional piece of information. The Australians passed a bill 3 years ago which put a moratorium on the creation of human embryonic stem cell lines in Australia, to await further developments in the field. The bill said that the science underlying the use of embryonic stem cells will be evaluated further at the end of three years. The prime minister of Australia appointed a commission to assess that science and the moratorium was allowed to lapse in the meantime, until the commission comes out with its recommendations.

            In terms of science, a lot will happen in three years. For example, I believe that there will soon be studies showing the embryonic stem cells can be cloned through fusion techniques without having to use an egg.

            In terms of politics, a lot may also happen in three years, including the possibility of an administration with a different political viewpoint. An overwhelming majority of American voters support embryonic stem cell research using in vitro fertilized eggs that are to be thrown out. In New Jersey, various polls have shown that 72-75% of voters believe that the state should fund human embryonic stem cell research.

            [This message was edited by Wise Young on 04-20-05 at 06:45 PM.]


              I assume by non-fertilized you mean an egg containing a somatic cell? Sounds good, but it won't fly for a few reasons. The biggest objection would be that a cloned embryo could be grown in a lab, with an equally strong objection to the fact that scientists would still be creating embryos just to destroy them. (Catholics won't yield on this point, so it's wasted breath debating it.)

              Assume there's a ban on using human eggs in SCNT. What avenues of research would then be unavailable to scientists?

     a diamond, in the rough
    's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.



                There is a general anti-cloning SCNT bill that was passed by the House of Representatives nearly 2 years ago and it awaits passage of the Brownback bill in the Senate to become law. In the meantime, a new bill to allow research on embryonic stem cells derived from IVF embryos that are about to be discarded as been proposed. I expect the following three legislative moves in Congress in the coming month:

                1. the President's Council on Bioethics will be recommending that a new regulatory agency be established solely for the purpose of regulating stem cell therapies and research. Of course, such a regulatory agency will be headed by an administrator appointed by the White House.

                2. Senator Sam Brownback will continue to press for passage of S.234 "A bill to amend the Public Health Service Act to prohibit human cloning" which prohibits human cloning, defined as "human asexual reproduction, accomplished by introducing nuclear material from one or more human somatic cells into a fertilized or unfertilized oocyte whose nuclear material has been removed or inactivated so as to produce a living organism (at any stage of develoopment) that is genetically virtually identical to an existing or previously existing human organism". The penalties include up to 10 years imprisonment and up to $1 million fine. Note that the House of Representative has already passed a similarly worded HR534 Human Cloning Prohibition Act of 2003.

                3. Senators Spector and Harkin introduced S471 IS Stem Cell Research Enhancement Act of 2005 which allows the Secretary of Health to "conduct and support research that utilizes human embryonic stem cells... (regardless of the date on which the stem cells were derived from a human embryo), if the stem cells were derived from human embryos that have been donated from in vitro fertilization clinics, were created for the purpose of fertility treatment, and were in excess of the clinical need of the individuals seeking such a treatment.... it was determined tha the embryos would never be implanted in a woman and would otherwise be discarded..." This is the bill that would allow embryonic stem cells from IVF embryos to be used and studied. The equivalent bill in the house is HR 810 IH, introduced by Representative Castle.

                So, the two bills on IVF embryonic stem cells (HR810 and S471 IS) will be voted on by the both the House and the Senate soon. Since the House already passed the Weldon bill (HR534 Human Cloning Prohibition Act of 2003), everything depends on the Senate passing the Brownback bill (S.234 A bill to amend the Public Health Service Act to prohibit human cloning).

                Three things may happen:
                1. Both HR810 and S471 IS pass and S.234 is defeated. This would allow embryonic stem cell research and there would be no federal law regarding cloning.
                2. Both HR810 and S471 pass and S.234 passes. This would allow embryonic stem cell research and SCNT will be banned.
                3. Either HR810 and S471 do not pass and S.234 passes. This would continue the current restrictions on embryonic stem cell research and SCNT will be banned.


                [This message was edited by Wise Young on 04-20-05 at 07:02 PM.]


                  Great write up. I firmly believe ESC research must be allowed to proceed forward. I am all for placing very strict penalties on any uses of reproductive cloning, I believe that to be unethical and a misuse of science. I am all for theraputic cloning though.
                  "Life is about how you
                  respond to not only the
                  challenges you're dealt but
                  the challenges you seek...If
                  you have no goals, no
                  mountains to climb, your
                  soul dies".~Liz Fordred


                    In my opinion to argue against SCNT is a mute point for those who believe the IVF process okay.
                    With the IVF process you are creating many embryos for the sake of one. Fertilization and conception take place.
                    With SCNT it does not. I don't get it. How can you justify one and condemn the other?
                    The argument that someone might clone a human is also a mute point. Ban reproductive cloning. As that stem cell biologist pointed out in his letter with a great analogy...after Sept 11 they didn't outlaw planes because someone might do something bad with them.



                      Weldon's bill from 2003 was passed last session and is no longer valid. A SCNT ban would require Weldon's new bill (HR1357) as well as Brownback's bill (S658) during the current session.

                      On the subject of this post in general, what you wrote is very good. I agree with Curt on all points.

                      But the question remains, what research would banning the use of an egg in SCNT prohibit?

             a diamond, in the rough
            's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.



                        My original post above was written in response to a request from Alan who wanted some justification for embryonic versus adult stem cells. By the way, I am not sure that I agree with you that everybody believes that embryonic stem cell research is valuable. Many people that I talk to simply don't want anything to do with something that has the word "embryo" in it.

                        Let me try to clarify some of the cloning comments that I wrote above below.

                        1. At the present, a cloned embryo cannot be grown in the lab and develop beyond the blastula stage. The stage requires implantation in a uterus.

                        2. The Catholic position on unfertilized eggs is not clear at least to me. The Evangelium Vitae by John Paul II in 1995 refers to fertilization as the beginning of life. More recent articles did not shed much light on how the Catholic Church regards an unfertilized egg that is making some stem cells.

                        3. Several people have tried to come up with ways to get around the issue of "killing" an embryo, to the point of absurdity. For example,
                        • John Hurlburt from Stanford tried to propose a genetic modification of the egg so that it cannot develop beyond the blastocyst stage. This method, assuming that it is feasible, uses a molecular agent to kill the egg at a particular stage of development.
                        • The second idea was to remove one cell from a blastocyst, based on the notion that it would not harm the blastocyst to have one stem cell removed. By the way, it is not feasible to take a frozen embryo, thaw it, remove one stem cell, and then refreeze the embryo. That has a high probability of damaging the egg or even killing it. So, it will have to be done to a blastocyst before it is implanted into a uterus. The chances of growing a stem cell line from one stem cell is vanishingly small. Yes, I know that there are some people who claim to have removed one cell from a blastocyst and carried out genetic analysis of the cell but I don't know anybody who has created an embryonic stem cell line from one cell removed from a blastocyst.

                        4. There are several possible alternatives to producing pluripotent embyro stem cell-like cells without necessarily harming a person or a potential person.
                        • John Gearhart discovered that fetal germ cells are pluripotent stem cells that behave very similarly to embryonic stem cells. It is possible to remove such cells from fetuses that have been spontaneously aborted.
                        • Recent studies suggest that stem cells will fuse with somatic cells. If one were to mix embryonic stem cells (say, obtained from one of the existing human embryonic stem cell lines) with somatic cells from a person (say, mononuclear cells from the blood), some of the mixed cells should fuse and some of the fused cells may behave like stem cells (Source). For example, Ying, et al. (2002) mixed mouse neural cells with pluripotent embryonic stem cells and found that the two cell types fused with each other and the resulting fused cells contained the genes of both sets of cells but that the cells behaved like pluripotent embryonic stem cells.


                        [This message was edited by Wise Young on 04-20-05 at 08:55 PM.]


                          Steven, sorry. I knew that the Weldon bill has to be passed again but mispoke. It passed by a considerable margin and I don't know how it will fare this time.

                          Hope, I agree with you that once one concludes that a blastocyst is not a person, a cloned blastocyst is also not a person. But, if one believes that a blastocyst is a potential person, it may still be okay to remove stem cells from a blastocyst that is about to be discarded. In such a case, the blastocyst was not created for harvesting its stem cells and the blastocyst would be killed whether or not the stem cells were removed. Cloning presents a different situation where the blastocyst was created for the purpose of harvesting its stem cells. This seems to make a big difference for people who opposed cloning and embryonic stem cells.

                          The only way to resolve this debate may be to develop ways to create pluripotent stem cells without utilizing eggs. If eggs were removed from the scene altogether perhaps this would satisfy opponents of the research. By the way, germ cells are stem cells that make eggs and sperms. Recent studies suggest that mouse ovaries continue to make eggs throughout their adult lives. In other words, there may well be stem cells that are pluripotent in adult human ovaries. Since ovariectomies are carried out in many thousands of women every year in the United States, perhaps this could a source of stem cells that could be used to create cloned stem cells.

                          Sigh. It is so difficult to guess what would satisfy the people who oppose the research. If they could accept this as ethical, scientists can go ahead to solve the problem. Believe me, scientists are trying hard to get around the restrictions and figure out a way to get a renewable and expandable source of cloned pluripotent stem cells. That is the goal.




                            My position on embryonic stem cells is that the debate over them for the past four years has wasted valuable time. I declined to contact Bush's campaign during the election about ethical alternatives to obtaining embryonic stem cells in the hope that a Democrat would win and overturn Bush's restrictions. I don't plan on having the next four wasted if I can help it, so I am speaking up.

                            Are embryonic stem cells valuable? Two or four years ago, sure. Now? Of course, but other promising therapies for spinal cord injury are closer to human application. The best thing to do now is to allow the research to move forward, and if SCNT (without the use of eggs) offers no benefits that cannot be obtained via alternative methods, the research can move forward.

                            I have spoken with a few of the people Sam Brownback brought in to defend his comprehensive cloning ban over the past week and they are okay with embryonic stem cell research. So are all of the upper echelon Catholics that I have spoken with. The only opposition they have is to the cloning, thus the reason I am focusing on SCNT and its offerings.

                            If you want to understand the Catholic position on cloning, use the following assertions as your basis:

                            1) A fertilized egg, or something phenotypically similar [eg, cloned embryo], has a soul. Stopping it's development is a sin.
                            2) Modifying the germ line [eg, enucleating an egg or nuclear transfer] is immoral and should not be done.

                            With these as your basic premises, the Catholic position is relatively simple to determine. You don't have to agree with these assertions, you just have to find a middle ground. Your points in #4 are excellent examples of how we can move forward with research that the Catholic Church will support.

                   a diamond, in the rough
                  's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.


                              Originally posted by Wise Young:

                              Hope, I agree with you that once one concludes that a blastocyst is not a person, a cloned blastocyst is also not a person. But, if one believes that a blastocyst is a potential person, it may still be okay to remove stem cells from a blastocyst that is about to be discarded.
                              Dr. Young...this is what really confuses me. If they really and truely believe that, then it seems to me there would not be any blastocysts to discard because IVF clinics would be banned on that line of reasoning.

                              I think I better post the link to the letter I made reference to. I posted it in the other topic, but others may not know what I was referring to if they are reading this one.
                              In referrence and with respect to the stem cell biologist I mentioned in my prior post:
                              Link to letter here