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New Therapies, No Cloning by Wolfgang Lillge, M.D. Most people around the world believe that embryonic stem cells offer the greatest promise for developing new medical treatments: In reality, adult stem cells from the body of the patient being treated, have shown a much greater potential for curing severe diseases. One reason for this distorted public opinion is the pattern of media reports about ongoing research with stem cells. Any new result, even if a very minor one, with embryonic stem cells, is blown up in the media as a major breakthrough. But when researchers announce even greater success using adult or alternative sources of stem cells, there are generally only small notes in the remote corners of the science pages. The same spin has an obvious political purpose, as it has a major influence on the current cloning debate, both in the United States and abroad. There is a powerful lobby, including biotechnology companies and investors, that is pushing hard to completely open up scientific research to the "therapeutic" cloning of human embryos, disregarding moral objections associated with it. While adult stem cell research continues—somehow anonymously, but with remarkable success!—the public focus is clearly on embryonic stem cell research. The current debate in the U.S. Congress on whether to allow cloning of human embryos for research purposes is a reflection of that. What is needed in the legislative process is a clear perspective about the consequences of such decisions. Scientists cannot achieve progress by overriding basic human values; here, this means developing treatments for diseases by killing human embryos in the process. One must understand there is no qualitative difference between cloning a human embryo for "therapeutic" means (to obtain embryonic stem cells) and for "reproductive" means (to produce a complete human clone). The difference is only technical; those who strongly favor therapeutic cloning should honestly admit to these consequences. The legislation in the United States is still undecided: The House has passed a strict cloning ban, which the President supports; many Senators are being lobbied and have come out for human embryo cloning for "medical research only." In Germany, such attempts remain banned, but the importation of stem-cell lines produced by this method from other countries, has now been permitted. In Britain, no restrictions exist on attempts at human cloning. What must be brought to bear is the informed moral stand of the citizens, against a further moral decline of society.
The Use of Stem Cells
Reviewing the research results of the last couple of years, it becomes obvious that embryonic stem cells involve severe problems when scientists try to use them as means of treatment. Largely unmentioned is the high "price" paid for these very uncertain results. To obtain embryonic stem cells, an embryo—a nascent human being—must be
killed in the morula phase of growth, when one can harvest "pluripotent" cells (i.e., those still able to develop into many different cell types). The general idea of therapy with stem cells, both embryonic and adult, is to use these cells to regenerate or replace diseased tissue, as in Parkinson's disease or multiple xclerosis patients. One of the major advantages of adult stem cells is that cells from the patient's own body can be used, which removes the risk of immune reaction against reimplanting these cells; whereas, in the case of embryonic stem cells, exogenous cells are used which definitely will provoke a major immune response. The only future way out of this immune dilemma would be to produce embryonic stem cells of the patient, by way of "therapeutic cloning." For that, you take a body cell, extract the nucleus, insert this nucleus into a denucleated egg cell, and stimulate its embryonic development. If it reaches the morula phase, you kill the embryo extracting the stem cells, which should be immunologically identical to the patient's cells. After culturing and transforming them into the needed tissue, they will be retransplanted to the patient for treatment. There has been, so far, no report of successful treatments of humans in this way. These cells seem to be too "unripe"—also reflected by the fact, that embryonic stem cells have a severe tumor risk. Of course, all these approaches are in a very early phase of research; but why pursue a technique where such problems are combined with a major moral handicap?
New Promising Results
The pattern of media twisting was visible recently when several important research results were achieved. Anyone who relies just on television for news, or quickly scans newspapers, would have missed them altogether. Using experimental procedures with adult stem cells, patients with Parkinson's disease and multiple sclerosis have experienced significant medical improvements. Comparable benefits using embryonic stem cell treatments have not yet been demonstrated even in animal experiments. The most recent case concerns a 57-year-old man, who was diagnosed at the age of 49 with Parkinson's disease, typified by a progressive loss of dopamine-producing cells in the brain. The disease worsened progressively, leading to tremors and rigidity in the patient's right arm. Traditional drug therapy did not help. As reported by neurosurgeon Michel Levesque of Cedars-Sinai Medical Center in Los Angeles, at a conference in Chicago in early April, stem cells were harvested three years ago from the patient's brain using a routine brain biopsy procedure. They were cultured for several months in the laboratory, growing to several million cells. About 20% matured into dopamine-secreting neurons. In March 1999, these neurons were injected into the patient's brain. Within three months the man's motor skills had improved by 37%, with an increase in dopamine production of 55.6%. By March 2000, the patient's overall performance had improved by 83%, and as of March 2002, no symptoms of Parkinson's disease can be seen—and that, without taking any other Parkinson's medication.
2 months. at a less severe stage of the disease. Six months after the first patient was treated. We may add a short list of other advances made in adult-cell therapies and research in the recent period: * In Israel. Similar treatments have also been tried in advanced stages of cancer. that had the treatment been conducted with embryonic stem cells. 26 people with severe MS underwent this treatment. Levesque will now expand his program to 12 additional patients. Conventional treatments had previously been unsuccessful for all of the patients. but there can be no question that the research is significant. after which she regained bladder control and the ability to wiggle her toes and move her legs. April 13-20. The new treatment involves removing stem cells from the patient's blood. * Immune systems destroyed by cancer were restored in children using stem cells from umbilical-cord blood. There is also a potential new treatment for people with severe cases of multiple sclerosis (MS). younger MS patients. Three other patients have also received successful adult stem cell grafts. After the stem cell transplant. "This is good news." Meanwhile in Canada. including recent therapeutic attempts using neural cells of aborted fetuses." said study author George Kraft of the University of Washington Medical Center in Seattle. she was found to have no evidence of the disease on MRI scans. either with no improvement or intolerable side effects. and then returning the healthy stem cells back to the body. Recent research results were presented during the American Academy of Neurology's 54th Annual Meeting in Denver. with no change in their amount of disability. so to get them to a point where they are stabilized is great progress. where strong chemotherapy would destroy the blood-producing system in the bone marrow. the media would have spread the story all over the place. then. * Harvard Medical School researchers killed cells producing insulin in mice. One can only assume. with no current evidence of active disease. 2002. "The hope is that these stem cells will eventually reconstitute into healthy immune system cells and the disease process can be stopped. There.Even if this is yet only a single case. called autologous stem cell transplantation. a treatment program on the basis of adult stem cells could soon outdo other approaches." said Kraft. Six showed some degree of mild improvement by some measures. Their results were followed for an average of 14. the animals' adult stem cells took over and regenerated missing cells . It is still too early to tell whether the Canadian patients have achieved permanent remission or a cure. killing those cells that are working against the body's immune system. 20 patients were stable. have shown even greater benefit from the same procedure. inducing diabetes. "These patients had all been rapidly deteriorating over the past year. doctors inserted white blood cells of a paraplegic patient into her severed spinal cord.
2001. injected into diabetic mice. or MAPCs—have the same potential as embryonic stem cells. The conditions of the experiment reported were such. Set-up has already begun for a trial for human patients at Massachusetts General Hospital in Boston. This compares to an experiment in which embryonic stem cells. Experiments so far seem to confirm that the cells—dubbed multipotent adult progenitor cells. and a Comparison with Adult Stem Cell Research Proponents of therapeutic cloning claim that this technique may offer a new mode of treatment in the repair and regeneration of tissue and organs. Verfaillie says that her lab has reliably isolated the cells from about 70% of the 100 or so human volunteers who donated marrow samples. of this astonishing success. "It should be possible to use the same method to reverse Type 1 diabetes in humans. Especially in the field of . to create a general doubt in public opinion. If further research confirms these findings. that no significant results could be expected. However. Nature Creates Doubts Against the mounting evidence in favor of adult stem cell treatments. with no signs of aging. but highly important note went almost unnoticed: Catherine Verfaillie at the University of Minnesota reported. said the British publication's note. that can turn into every single tissue in the body. "The permanent reversal of Type 1 diabetes in mice may end the wrenching debate over harvesting stem cells from the unborn to treat adult diseases. that she had found stem cells in the bone marrow of adults. implying that hopes for this research and practice may be premature. soon turned out not to be very convincing." said the Harvard University Gazette of July 19. Therapeutic Cloning: An Unnecessary Risk Characteristics. In contrast.needed to produce insulin and eliminate the disease. and all the mice died. they may be just fusing with other cells to form abnormal hybrids. the associate professor of medicine who leads the research. and later the authors themselves admitted that fusion of this type is a very rare event. there would be no need to resort to "therapeutic cloning" of human embryos in order to get matching stem cells. which are mistaken for pristine new tissues. the Nature warning was multiplied widely enough in leading nonscientific media. What seemed a strong argument on first view. achieved a 3% insulin production rate. The claim that adult stem cells are just as versatile as embryonic ones may have been misleading. a small. some cell lines have been growing for almost two years and have kept their characteristics. Until now. She reports the cells seem to grow indefinitely in culture. like embryonic stem cells." says Denise Faustman. a note was published in Nature magazine in March. only stem cells from early embryos were thought to have such "pluripotent" properties.
"therapeutic" cells (such as nerve cells. "The ethical validity of using nuclear transfer in human transplantation". human embryonic stem cells (hESCs) may be grown in the laboratory. will divide to form a population of identical cells. A single cell. claim that this view is incorrect.organ transplantation. When the egg has developed into a blastocyst. however. 284. in other words) of a human embryo. which gave rise to Dolly the sheep). in the event that the donor might need such treatment at a future date. and then implanted into a surrogate woman who ultimately gives birth to a clone of the man from whom the skin cells were derived. muscle cells. organ tissue. along with a myriad of other complexities and problems.. from an adult female. The way in which this is done is as follows. Skin cells may then be removed from an adult male. From this cloned embryo. and the controversies surrounding such means. the DNA may be removed from a harvested egg (thus "enucleating" the egg). that the cloning may be used for reproductive purposes instead of for "therapeutic" purposes. The resulting cloned embryo is therefore genetically identical to the donor. healthy. which are grown to produce the desired. however. "It is true that the techniques developed in CRNT research can prepare the way scientifically and technically for efforts at reproductive cloning. Critics. this characteristic of identical genetic matching has been considered the primary advantage of "therapeutic" cloning. known as cell clones. Other names for therapeutic cloning include Somatic Cell Nuclear Transfer (SCNT. where immune rejection is common. 12/27/2000). A somatic (adult) cell from the donor is transferred into an enucleated egg (an egg from which the nucleus has been removed). It is possible. . According to Dr. cultured in a dish by itself. in order to avoid immune rejection). Robert Lanza. and the DNA of these cells may be transferred into the nucleus of the woman's unfertilized egg. therapeutic cloning is often seen as a way of eliminating this problem of immune rejection." (Robert Lanza et al. there is evidence to prove otherwise. therapeutic cloning requires the deliberate creation and disaggregation (destruction. however. are inseparably linked. Until very recently. Although "reproductive cloning" and "therapeutic cloning" have different objectives. the means by which they are conducted. Whichever name is used. For example. to produce an early stage embryo with the donor's DNA. etc.3179. the inner cell mass is then removed and cultured into embryonic stem cells. Needless to say. yielding a single celled cloned embryo. In therapeutic cloning. 3175 . and that immune rejection still exists in therapeutic cloning. reproductive cloning is already widely recognized to be an ethical can of worms. These new cells are then transplanted back into the patient (who is presumed to be the same as the donor of the original somatic cell. Now. and Cell Replacement through Nuclear Transfer (CRNT). JAMA. This is how Dolly the sheep was produced.). stem cells are created from a donor for the main purpose of providing tissue (such as for organ repair).
However. He points out that even apparently healthy clones have abnormalities in gene expression. Dr. Even Dolly the sheep was "born" with incomplete epigenetic reprogramming (the heritable erasure and remarking of genes that determines either normal or abnormal development). 4/28/02). But there are also many other ways in which cloning places women at risk. Currently. Allowing for 10 eggs harvested per donor. Success rate = 3. One of the risks for the surrogate mother presented by cloning is what is known as "large offspring syndrome". in which the cloned embryo develops into an abnormally. large fetus by the time of birth. He also cites Ian Wilmut.S. and in most species the success rate is below 1%..Ethical controversies aside.5%. David A. every one of them. Success rate = 0. as 277 nuclear transfers were required to enucleated the eggs from which Dolly the sheep was created. adds that cloning is unsafe both for the clone and for the surrogate mother. without exception. Success rate = 0. Prentice has made some sobering calculations. Cloned cattle: 30 live births out of 496 cloned embryos implanted. Cloned mice: 5 live births out of 613. and dangerously.000 genes that were analyzed in cloned mice. suffers from numerous genetic abnormalities." he says. approximately 400 of these genes were found to express genetic abnormalities.D. Prentice.8% Cloned pigs: 5 live births out of 72 cloned embryos implanted. the highest efficiency rate of SCNT cloning in any species is 7% (with pigs). as well as a generous 10% efficiency at initiating the embryonic stem cell culture. Success rate = 0. Success rate = 6%. in order to treat all of the 17 million people in the U. For example. Cloned rabbits: 6 live births out of 1852 cloned embryos. The success rate of reproductive cloning is extremely low. who suffer from diabetes. Cloned goats: 3 live births out of 85 cloned embryos implanted.4%. Sunday Times of London. Ph. "There is abundant evidence that cloning can and does go wrong and there is no justification for believing that this will not happen in humans. however.5%. Success rate = 7%.3%. who points out that." (Quoted in "Gene defects emerge in all animal clones". and allowing for a generous 20% cloning efficiency to achieve the blastocyst stage. Success rate = 0. Success rate = 0. the first cloned animal: 1 live birth out of 277 cloned embryos. It has been pointed out that even when animals are successfully cloned. "A review of all the world's cloned animals suggests that every one of them is genetically and physically defective. Dr. even when successful. which translates into 85 million women of childbearing age who would be required as donors. of the Department of Life Sciences at Indiana State University. Cloned cat: 1 live birth out of 188 cloned embryos. This would be more than one-third the population of the United . Prentice offers some further alarming statistics on the success rates (or the lack thereof) of cloning in animals: • • • • • • • • Dolly the sheep. a minimum of 850 million eggs would be required. from 10. Cloned gaur: 1 live birth out of 692 cloned embryos.1%.
The process is a nonstarter. 2/13/2002. 3/8/2002). Alan Trounson. and this is unlikely. Prentice concludes.. Thomas Okarma. particularly if hundreds are required to produce each embryonic stem cell line. Overall.M. stating that. 2001). who would be needed as egg donors for the treatment of a group of people roughly one-sixteenth as large in population size. Drs. Rideout et al. "The derivation and potential use of human embryonic stem cells". "The odds favoring success are vanishingly small. Prentice adds. "Our results raise the provocative possibility that even genetically matched cells derived by therapeutic cloning may still face barriers to effective transplantation for some disorders." (Quoted by Denise Gellene in." an online publication in Cell. commercially." (Odorico JS. While high dose hormone therapy and surgery have been developed to obtain eggs in large numbers. Kaufman and Thomas have written. Dr. John Gearhart have both stated before the President's Council on Bioethics that transplant rejection will still occur. "Clone Profit? Unlikely". "The technical capability for nuclear transfer would also need to be widely available. Alan Trounson adds. Dr. before the President's Council on Bioethics. Dr. Additionally. before the President's Council on Bioethics). such techniques nevertheless pose significant health risks by jeopardizing the donor's immediate health and future reproductive success." he says. 4/25/2002. 2001. Corroborating such a view. "Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. and Drs. Dr." Stem Cells. even though the cells from the cloned embryos are considered "genetically identical" to the donor. "Multilineage differentiation from human embryonic stem cell lines". 2001). It has been proposed by a number of researchers that cloning is not able to provide the claimed medical treatments. therapeutic cloning may be judged as unsuccessful. Irving Weissman. the low efficiency of the nuclear transfer procedure. 5/10/2002). (Dr. Stem Cells. Dr. Los Angeles Times. Dr." (W. James Thomson. Odorico. It would take thousands of [human] eggs on an assembly line to produce a custom therapy for a single person. Transplantation remains one of its many problems. has pointed out that cloning is not commercially viable.States. Thomson JA. Reproduction. that it is unlikely that large numbers of mature human oocytes would actually be available for the production of embryonic stem cells. and Dr. Dr. Additionally. the possibility for commercial exploitation puts economically disadvantaged women in particular jeopardy. . and the long population doubling time of human embryonic stem cells make it difficult to envision this becoming a routine clinical procedure. James Thomson and Alan Trounson add that there is a very low chance of success in the clinical use of therapeutic cloning. Fertility and Development. Kaufman DS.M. John Gearhart. Rideout as having stated. "Multilineage differentiation from human embryonic stem cell lines. however. and Dr. CEO of Geron Corporation. Prentice cites W. "The poor availability of human oocytes. and the costs are daunting. Irving Weissman of Stanford University. (Dr.
" Reproduction. The versatility of adult stem cells is thus much greater than originally thought. AAP Newsfeed. will be required for that. Although it is possible to customize embryonic stem cells by therapeutic cloning or cytoplasmic transfer." he states. has stated that cloning has now become "unnecessary and obsolete". says scientist". and delay cures. "Therapeutic cloning no longer necessary: expert". Irving Weissman of Stanford University stated in his testimony before the President's Council on Bioethics. Even the previously assumed multipotency and monopotency of adult stem cells is now being challenged by more recent data. He says that stem cell research has advanced so rapidly. which must remain a concern for embryonic stem cells derived by nuclear transfer. you would argue for therapeutic cloning in the long term. Cloning research will divert resources away from other. Trounson. Fertility and Development. that therapeutic cloning is now unnecessary. • . the mitochondria still come from the host. Emphasizing the point that therapeutic cloning faces too many "logistical problems. 7/29/2002)." Dr. 7/29/2002. Many experts are now extolling the promise of regenerative medicine through stem cells. Dr. just in the past few months alone. 2/13/02. As Dr." In light of this realization. "I should say that when you put the nucleus in from a somatic cell. before the President's Council on Bioethics). The Australian. more worthy areas of research. "My view. And in mouse studies it is clear that those genetic differences can lead to a mild but certainly effective transplant rejection." (Alan O. "The derivation and potential use of human embryonic stem cells. he has abandoned his own work in therapeutic cloning. Arguments against human cloning include: • • There is no evidence that cloning is necessary or useful for medical treatments. epigenetic remnants of the somatic cell used as the nuclear donor can cause major functional problems in development." ("Stem cell cloning not needed. The Age [Melbourne]. Alan Trounson. mild though it is. 7/29/2002. "Stem cell research outpaces cloning". turning his attention instead to the more promising field of stem cell research. "is that there are at least three or four other alternatives that are more attractive already. 2001). then. it would appear unlikely that these strategies will be used extensively for producing embryonic stem cells compatible for transplantation. Irving Weissman. Trounson adds."In addition." and that other techniques show "greater promise" and offer "better options." (Dr. instead of through therapeutic cloning. "I can't see why. because it is so difficult to get eggs and you've got this issue of [destroying] embryos as well. Banning only implantation (reproductive cloning) is unenforceable. the Australian embryonic stem cell expert and a globally recognized leader in the field. which have demonstrated that some adult stem cells are capable of exhibiting pluripotency. and so immunosuppression.
so researchers are still trying to determine the specific types of tissue into which the cells will grow. despite the fact that additional chemicals were used to "jump start" the cellular division. . only onefourth of the SCNT eggs successfully reached the blastocyst stage (at which point the inner cell mass was harvested to create hES cells). From a total of 30 blastocysts. a report issued in February of 2004 from South Korea highlights the difficult logistics of human cloning. for purposes of growing "customized" stem cells for replacement tissue in the treatment of disease. and they were then given hormone injections to induce superovulation. could. theoretically. Cloning may possibly lead to the commodification and commercialization of human life. However. The bioethics of such research has triggered debate among scientists and politicians worldwide. grow into cloned babies. was quoted as saying. Even beyond the ethical questions. if transferred into a woman's uterus. Each volunteer also donated some cells directly from one of her ovaries. were the first to successfully clone a human embryo. The results were published in the U. A further complication is the fact that it is not yet fully understood how to control the direction of hESC growth. Even Alan Colman. and they raised questions over how rigorously Hwang and his colleagues had followed the ethical guidelines imposed upon their research. The report describes the first successful attempt to create a hES cell line by SCNT. but only one ES cell line was successfully obtained. From the cumulus cells surrounding the developing oocyte (the immature egg cell). a goal which continues to remain elusive. there still remain concerns that therapeutic cloning is too inefficient and too expensive.• Cloning creates a class of human beings who exist only as a means to achieve the ends of others. that attempts by the South Koreans to clone male cells failed. "I do not welcome this. the nuclei were transplanted to the egg of the same individual. Researchers at the South Korea Seoul National University. Cloning is the "gateway" to genetic manipulation and control of human beings. It was noted. however. Journal Science." Cloned embryos. Sixteen (unpaid) women voluneteers had been recruited for participation in the study. 20 inner cell masses were harvested. Hwang Woo Suk. Cloning risks the health. Citizen's rights activists and bioethicists complained of the lack of transparency surrounding the recruitment of the egg donors. Donor and recipient were therefore the same. • • • Additionally. and began forming muscle. in a study led by Dr. presumably eliminating the risk of immunological rejection. using the same process as that used in the cloning of animals. The cells in this ES cell line are genetically identical to the donor. which resulted in the production of 242 eggs that were used to produce the single hES cell line. one of the experts on Dolly the sheep.S. safety and possible exploitation of women. bone and other tissues in test tubes and when implanted into mice.
for behind the mirage of a coming medical wonderland. the much extolled vision of the future turns out to be a case of completely empty promises: Given the elementary state of research today. the manipulation of germ lines. it is supposed to be "acceptable" to "overlook" a few moral problems. therapeutic cloning may correctly be viewed as unsafe. promoted by interested parties. The greatest hope for clinical regenerative medicine may therefore be found in postnatal and adult stem cell research. destroying the embryo. Basically. to develop into almost all of the different types of cells. whether even one of the hoped-for treatments can be realized. In the process. under suitable conditions. no one can escape the fact that. unethical. Alzheimers. could then be alleviated or healed. On closer inspection. It is remarkable that in the debate–often carried on with little competence–the potential of embryonic stem cells is exaggerated in a one-sided way. for which there are as yet no effective therapies. and so forth. including for cardiac infarction (death of some of the heart tissue). The question of stem cells is currently the dominant subject in the debate over biotechnology and human gen use embryonic stem cells or adult stem cells for future medical therapies? Embryonic stem cells are taken fro embryo at the blastocyst stage. Generally. and unnecessary. or revert to being stem cells with greater reproductive capacity stem cells have not yet been used for even one therapy. Perfect candor should rule in stem cell research. according to latest reports. and the like–thus for everything other than therapeutic purposes. Any coverup or hypocrisy in this matter will very quickly reflect upon the research as a whole. . however. a developing human life. while important moral questions and issues of research strategy are passed over in silence. should one wish to use embryonic stem cells for "therapeutic purposes." the very techniques will be developed that will also be used for the cloning of human beings. while adult stem cells have already been successfully numerous patients. completely other research objectives will be pursued that are to be kept out of public discussion as much as possible. Faced with such a prospect. on the othe found in all tissues of the growing human being and. it is by no means yet foreseeable. AIDS. Adult stem cells. multiple sclerosis. such promised cures are a deliberate deception. Stem cells are of wide interest for medicine. also have the potential to tran themselves into practically all other cell types. destroyed insulinproducing cells in the pancreas). This requires that the scientist himself clearly establish the moral limits of his activity and declare what the consequences of research with embryonic stem cells really are. the making of human-animal hybrids. They should therefore be able to repair damaged or defective tissues (for example. advocates of research with embryonic stem cells use as their main argument that such research will enable us to cure all of the diseases that are incurable today–cancer.In summary. because they have the potential. Many of the so-called degenerative diseases.
" That is. as soon as a cell has reached a certain degree of "maturity. toward increasingly "mature. which then continue to develop into the embryo proper–have this pluripotential. but never backward. This process is supposed to run only forward. from which all the other kinds of blood cells develop. which is capable of developing into a complete organism. a stem cell is one that–in the course of cell division and increase in the numbers of cells–is able to reproduce itself and also mature into various specialized types of cells. and the overthrow of some dogmas of developmental biology." the way back to earlier stages of development is closed off. Thus. So it is evident that a stem cell’s capacity to perform is increasingly limited to specific functions. however. they can form many different types of tissues. and in later stages the cells retain only "pluripotential. the fertilized egg cell has totipotential up to the stage of division into eight cells. neuronal stem cells of mice have transformed themselves into blood stem cells and produced blood cells. The stem cell with the greatest potential (totipotential) is the fertilized egg cell. In the course of further specialization. According to the usual–but actually very doubtful–explanation. to take on the cell functions of the new tissue. in the development of the individual. but they can even assume more generalized. so that it even appears possible that they become totipotent again. According to latest reports. Exactly? It is appropriate here to sketch the characteristics of stem cells. from totipotentiality to tissue specificity. those 50 cells within a blastocyst." Not only can they adjust to the specific conditions of a new tissue environment. . That is. correspondingly. Embryonic stem cells–that is. this dogma of developmental biology does not hold. such as that of the bone marrow." specialized cells in the individual tissues. earlier levels of development. there are indications of another capability of adult stem cells: Apparently they have the potential to be "reprogrammed. Broadly speaking.What Are Stem Cells. Evidently. the manifold capabilities still present in earlier developmental stages. but not the complete organism. stem cells of individual tissues are formed. Indeed. tissue-specific stem cells have the ability–as has been impressively demonstrated in experiments with animals–to "transdifferentiate" themselves when in a different environment–that is. Behind this description lies the conception that a linear process of differentiation is played out. and it loses.
Normally it goes unmentioned. and here is the basis for the widespread fear that the same method that is used for "therapeutic cloning" can also be used for the selective breeding of humans.Laboratory Virola in Ukraine has demonstrated that bone marrow stromal cells in culture are pluripotent–that is. there must not be a single undifferentiated cell. the production of which has been extremely controversial. and it then develops into the blastocyst. In addition to the obvious moral consideration. That is in no way sufficient for cell transplantation as a human therapy. it is also not possible to produce sufficiently pure cell cultures from stem cells. "Dolly." The only difference is that the development of the embryo is not interrupted in the early blastocyst stage." the first cloned sheep. the embryo is destroyed. Problems of ‘Therapeutic Cloning’ Until now. in this case to the formation of teratomas. from which stem cells can be removed. was produced by this method." so called. a human egg cell is denucleated. In a cell culture for therapeutic purposes. and so on. So far. So far there has been no solution to the problem of developing in the laboratory an unmistakable identifier for stem cells that can distinguish them unequivocally from cancer cells. cartilage. that it is only a small step from this so-called "therapeutic cloning" (because. with embryonic mouse stem cells. talk of a possible source of human replacement tissue has centered on embryonic stem cells. instead the embryo is implanted in a uterus and a complete organism develops–an exact genetic copy of the donor. bone. that is. and in its place is put the nucleus of a somatic (body) cell. because in obtaining them from a human embryo produced by artificial fertilization in vitro. The danger of tumors. it is claimed. This problem would not be expected with adult stem cells. since it can lead to unregulated growth. fat." In principle. in this way a therapy for diseases can be developed) to what is called "reproductive cloning. because of their greater differentiation. Researchers at this laboratory have developed techniques to differentiate in vitro mouse bone marrow stromal cells into different types of neuronal and glial cells. a purity of only 80 percent has been achieved. the DNA is removed. a cancerous tumor derived from the germ layers. The egg cell is stimulated with a short electrical pulse. For this reason. These are identical with those of the donor of the somatic cell nucleus. The laboratory is seeking funds to develop similar methods for human bone marrow stromal cells. there are still other serious disadvantages that make this path to the development of human "replacement parts" appear to be untenable. They are a typical product of "consuming embryonic research. . The most important research technique for which such embryos are obtained is "therapeutic cloning. they are able to differentiate into cells of liver.
and his colleague. There were no two clones in which the same pattern of gene activation was found. and develop them to the point that they form mature cell types with the help of growth factors and regulating proteins. and of those born alive. adult stem cells would promise a very productive research field–and beyond that. muscle. This knowledge must be brought into the public consciousness with all possible emphasis. This shows that in tissues of the body. reprogramming them was considered impossible. In recent years. are activated. and Jaenisch is convinced that the use of embryonic stem cells was clearly responsible. so that not all of the genes that are necessary to the early phase of embryonic development. when the nucleus of a somatic cell is inserted into a denucleated egg cell–the reprogramming of the genes does not proceed properly. That is. Jaenisch performed his experiments with mice that had been cloned using embryonic stem cells in place of the somatic cells. in the mesenchyme (connective tissue) of various organs. the reprogramming of the inserted genetic material by the embryonic cells proceeded in a very unregulated way. but it was assumed that they could only form cells of a particular tissue. not even half survive for three weeks. Moreover. in the brain. but the probability of their having numerous genetic defects is very high. But to his surprise. and nerve cells. One of the reasons for this high failure rate has now been discovered by the German scientist Rudolf Jaenisch at the Institute for Biomedical Research at the Massachusetts Institute of Technology. probably every clone would have subtle genetic abnormalities that would frequently become noticeable only later in life. adult stem cells possess a much greater potential for differentiation than previously assumed. What consequences follow from this for the therapeutic use of human embryonic stem cells–consequences that will in fact be multiplied through cloning–are not yet foreseeable. These pluripotent stem cells are capable of forming several cell types–principally blood. without moral objection. It has been possible to recognize. Cloned animals like Dolly give the outward appearance of full health. Their conception is that in cloning–that is.Genetic instability. there is a success rate of 3 to 4 percent. to discover fundamentals of the dynamics of tissue differentiation. If stem cell research were really only meant for therapeutic uses. and in the blood of the umbilical cord. pluripotent stem cells were discovered in various human tissues–in the spinal cord. Only recently a further problem has emerged. Whoever Would Cure. select. Fundamental doubt of the suitability of embryonic stem cells for transplantation has come to the surface because of the genetic instability of cloned cells. a possibility. In the best case. which it most obviously should be. Most cloned animals die before birth. the entire cloning procedure is extremely ineffective. Ryuzo Yanagimachi. Must Use Adult Stem Cells It has been known for about 30 years that stem cells are present in the tissue of the adult. Even when cloned animals survive at all. which produces better results. however. .
spectacular experiment was reported. the doctors took bone marrow from the patient’s pelvis using local anesthesia. If these observations are correct and are confirmed by other teams of scientists. because the cells are from the same body. He was able to prove that adult stem cells of blood-forming tissues. the doctors could not yet take cardiac tissue to prove definitively that the implanted blood stem cells had converted to heart muscle cells. with similarly positive results. Human Treatments Moreover. that stem cells of a particular tissue can develop into cells of a completely different kind. Prof. they treated a cardiac infarct patient with stem cells from his own body. lung. The functioning of the severely damaged heart clearly improved within a few weeks. a team of doctors at the Duesseldorf University Clinic carried out a treatment of very far-reaching consequences. The treatment comes into play when. and makes them mutually interchangeable. and are able to resume the formation of blood cells. The special advantage is that there are no rejection reactions. for example. a patient has lost his or her blood-forming tissue through radiation or high-dose chemotherapy. and of the brain.It has become clear from transplantation experiments with animals. Adult stem cells obviously have a universal program for division that is common to all the kinds of tissue stem cells. For the first time. which was carried out on mice by scientists at Yale University. The cardiologist. Four days after the infarction. but also liver cells. Bodo Eckehard Strauer. Previously removed bone marrow stem cells are then retransplanted. according to Strauer. The researchers obtained stem cells from the bone marrow of male mice. In May 2001. is sure that the stem cells from the patient’s bone marrow. but also in their blood. there is no other way to explain the marked improvement in the patient’s condition. after injection into the infarct zone. in order to preserve their status as stem cells. However. autonomously converted to heart muscle. Of longer standing is treatment with bone marrow stem cells. six more patients have already been treated with their own stem cells. . This was discovered by Alexei Terskikh at Stanford University School of Medicine in California. the male stem cells (identifiable through the male Y-chromosome) were found not only in the females’ bone marrow. science should concentrate on research with adult stem cells and renounce further experiments with the embryonic. Eleven months later. and in their gut. activate the same genes. In 2001. Thus. After this first successful operation. But. a further. The stem cells in the marrow were concentrated outside of the body and implanted in the infarct area the next day with a special technique via a coronary artery. however. very promising treatments of serious diseases with adult stem cells have already been tried. bone marrow stem cells have been induced to become brain cells. and injected it into females whose own marrow had been destroyed by radioactive irradiation. and skin tissues.
compared to a previous rate of 5 percent at best. and are hard to find with the techniques used so far. Only a few papers and meeting reports have emerged from the handful of labs that work with human pluripotent cells. they reported obtaining a culture of 80 percent purity. . the human embryonic stem cells and fetal germ cells that made headlines in November 1998 because they can.There are also reports of successful treatments with adult stem cells in cases of Crohn’s disease (a chronic infection of the gut). What is Vet-Stem Regenerative Medicine? Regenerative medicine uses a concentrated form of autologous adipose-derived adult stem cells to treat traumatic and degenerative diseases. 412. Success in numerous animal models of disease and emerging success in human clinical trials for Crohn's fistulas1 and stroke2. in theory." This is the restrained language used by established science to describe a truly disastrous set of results. thalassemia (a blood disease). including bowed tendons. . It is now urgently necessary to tackle the research in precisely this direction. . of course. reports of successful conversions of embryonic stem cells are very infrequent and cautious. And–despite the fact that basic research with adult stem cells is in its earliest beginnings and is in no way being promoted with urgency–there have been a growing number of reports lately of experiments with animals. Thus. it proceeds. osteoarthritis. 290. and a rare skin disease. Success in human clinical trials and animal models Despite its infancy. . develop into any cell type have so far produced relatively modest results. In Nature of August 16. pp. still substantial problems to be overcome. It was therefore an important advance that Australian researchers of the Walter and Eliza Hall Institute of Medical Research have now found a way to isolate nerve stem cells with "extreme purity" from the brains of mice. even with adult stem cells: They are relatively rare. from which it emerges that adult stem cells can successfully transform themselves into differentiated cells of organs of many kinds. pp. ligament injuries. The work suggests that it will not be simple to produce the pure populations of certain cell types that would be required for safe and reliable cell therapies. There are. heretofore incurable diseases. . In contrast. 736-739). regenerative medicine is not new. Only by this morally unassailable route will it be possible to develop new therapies for serious. in order to find out the exact conditions under which the differentiation of stem cells comes about and how. and osteochondral defects in horses and dogs. along with hundreds of ongoing clinical trials (See sidebar) support the rationale . 1672-1674): "In contrast. 2000 (Vol. 1. to improve our understanding of the development of life itself. and beyond that. we find in Science of Dec. 2001 (Vol. in detail. They are also not very easy to culture outside of the body. .
and fractures. and in dogs with osteoarthritis More than 2. blood vessels.5% local tissue reactions. The stromal fraction that is harvested from adipose tissue is a heterogeneous mixture of regenerative cells (see below). Vet-Stem collaborative and clinical research demonstrate positive results in treating horses with tendon and ligament injuries.3-6 Stem cells are multipotent and can differentiate into tendon. Sunnyvale.for stem cell use.4 . osteochondral defects..3-6 Demonstrated efficacy with VSRC therapy in horses and dogs o Cornell University double-blind. cardiac. ligament injuries. placebo controlled study5 o Retrospective studies3. muscle. 23 (see figure below).000 horses treated since 2003 No systemic adverse events reported and < 0. and liver tissue22. • • • • • • • Rationale based on consistent therapeutic success in numerous animal models of disease (see sidebar) Adipose-derived adult stem cells (Vet-Stem Regenerative Cells: VSRC™) Autologous cell therapy Currently used in horses with bowed tendons. Original patents from University of Pittsburgh and Duke University. fat. ligament. nerve. and osteoarthritis. CA. cartilage. and now success. in veterinary medicine. bone. Vet-Stem Technology: Summary Vet-Stem Regenerative Cell Therapy is based on a clinical technology originally licensed from Artecel Inc.
are maintained by tissue-specific stem cells. and function25 Stem Cells as Vehicles for Gene Therapy Stem cells can be classified as embryonic or adult.g. Specific surface .5 Although they are relatively rare in the human body. renal disease) Regenerative cells can differentiate into many tissue types. cartilage. depending on their tissue of origin. fracture) or are delivered systemically (e.4. creating the optimal environment for natural healing25 Regenerative cells produce a variety of both secreted and cell surface substances that regulate tissue growth. including:23 o Mesenchymal stem cells o Endothelial progenitor cells o Pericytes o Immune cells o Fibroblasts o Other growth factor-secreting bioactive cells Differences in Regenerative Medicine compared to traditional medicine. integrity. The role of adult stem cells is to sustain an established repertoire of mature cell types in essentially steady-state numbers over the lifetime of the organism. and intestinal epithelium. The prototypic example of adult stem cells. and stimulate regeneration22 Regenerative cells "communicate" with the cells of their local environment through paracrine and autocrine modalities. the stem cells themselves rarely divide.: liver disease.: tendonitis. has already been demonstrated to be of utility in gene therapy. and cardiac repair23 (See figure above) Fractions isolated from adipose tissue contain a heterogeneous mixture of regenerative cells. these cells can be readily isolated from bone marrow or after mobilization into peripheral blood. the hematopoietic stem cell. skin. desmitis.o Case studies6 Why use adipose-derived regenerative cells rather than regenerative cells derived from bone marrow? Adipose-derived regenerative cells are: • • • • Readily available source Can be collected in far greater concentrations than those from bone marrow24 Able to differentiate into multiple lineages implicating their potential in bone. such as during tissue repair after injury or following transplantation. Although adult tissues with a high turnover rate. However. stem cell divisions may become more frequent. induce repair. • • • • • Does not rely on a single target receptor or a single pathway for its action Regenerative cell mixture is delivered either directly to the traumatic wound (e.g. in certain situations. such as blood.
Another major limitation of using adult stem cells is that it is relatively difficult to maintain the stem cell state during ex vivo manipulations. where they travel automatically to the place in the bone marrow in which they are functionally active. After in vitro manipulation. One type of retroviral vector was initially employed to show proof-of-principle that a foreign gene (in that instance the gene was not therapeutic. hepatocytes (liver cells). In extreme cases. the multipotent adult progenitor cell. before being returned to them. but was used as a molecular tag to genetically mark the cells) introduced into bone marrow cells may be stably maintained for several months. the in vitro process is typically referred to as an quot.markers allow the identification and enrichment of hematopoietic stem cells from a mixed population of bone marrow or peripheral blood cells.8 The traditional method to introduce a therapeutic gene into hematopoietic stem cells from bone marrow or peripheral blood involves the use of a vector derived from a certain class of virus. and retransplanted into the same patient (autologous transplantation) or a different patient (allogeneic transplantation) retain the ability to contribute to all mature blood cell types of the recipient for an extended period of time (when patients' cells are temporarily grown quot. these cells may be retransplanted into patients by injection into the bloodstream.9 However. Under current suboptimal conditions. has been isolated from bone marrow that can differentiate into multiple lineages.7 Other adult stem cells have been identified. bone. because the gene therapy vector can potentially modify the activity of neighboring genes (positively or negatively) in close proximity to the insertion site or even inactivate host genes by integrating into them. efficiency was rather low. approach). a related stem cell type. such as those in the central nervous system and heart. adipose (fat) tissue.6 Recently. these particular retroviral vectors were only capable of transferring the therapeutic gene into actively dividing cells. In principle. which has the ability to form cartilage. The major drawback of these methods is that the therapeutic gene frequently integrates more or less randomly into the chromosomes of the target cell. but these are less well characterized and not as easily accessible. and other cell types. These phenomena are referred to as quot. called a retrovirus. adult stem cells tend to lose their stem cell properties and become more . in vitro manipulated. Since most adult stem cells divide at a relatively slow rate. ultimately resulting in cancer. including neurons. these mutations contribute to the malignant transformation of the targeted cells. endothelial cells (such as the cells that form the lining of blood vessels). Another adult bone marrow-derived stem cell type with potential use as a vehicle for gene transfer is the mesenchymal stem cell. this is dangerous.insertional mutagenesis. since they also target non-dividing cells.outside the bodyquot. Hematopoietic stem cells that have been explanted. such as in the X-linked SCID gene therapy trials. and marrow stroma (the bone marrow microenvironment). Vectors derived from other types of retroviruses (lentiviruses) and adenoviruses have the potential to overcome this limitation.ex vivoquot.quot.
c) and the establishment of protocols that allow the genetic modification of these cells. In these experiments. The nucleus of an egg cell was replaced with that from a skin cell of an adult mouse with the genetic immunodeficiency.differentiation. This gene may either be active or awaiting later activation. human embryonic stem cells are easily accessible for controlled and specific genetic manipulation.15 Skin cells from an immunodeficient mouse were used to generate cellular therapy that partially restored immune function in the mouse. Even after months and years of growth in the laboratory. These properties reflect their origin from cells of the early embryo at a stage during which the cellular machinery is geared toward the rapid expansion and diversification of cell types.quot. cells and transplanted into . at least in certain fields. once the modified embryonic stem cell has differentiated into the desired cell type.14 Much of the anticipated potential surrounding human embryonic stem cells is an extrapolation from pioneering experiments in the mouse system. hematopoietic. Two possible scenarios whereby human embryonic stem cells may benefit the gene therapy field are discussed below. this impact includes: a) differentiation of human embryonic stem cells into various cell types. Experiments performed with human embryonic stem cells in the last couple of years indicate that these cells have the potential to make an important impact on medical science. embryonic stem cells were generated from an immunodeficient mouse by nuclear transfer technology. pancreatic.gene targeting.11 Embryonic Stem Cell: "The Ultimate Stem Cell" Embryonic stem cells are capable of unlimited self-renewal while maintaining the potential to differentiate into derivatives of all three germ layers.curedquot.10. cardiac. and placental cells. Recent advances in supportive culture conditions for mouse hematopoietic stem cells may ultimately facilitate more effective use of human hematopoietic stem cells in gene therapy applications. human embryonic stem cells could be genetically manipulated to introduce the therapeutic gene. The Potential of Human Embryonic Stem Cells for Gene Therapy Following derivation. and ability to mature in vitro into multiple cell types of the body.stemquot. When this facility is combined with their rapid growth. The genetic defect was corrected by a genetic modification strategy designated quot. In particular. vascular. and finally human embryonic stem cells. hepatic. remarkable stability. The egg was developed to the blastula stage at which embryonic stem cells were derived. giving rise to mature cell types through a process termed quot. First.12. Recently published reports establish the feasibility of such an approach. These quot.specialized. b) the derivation of new cell lines under alternative conditions.13 and paved the way for the isolation of nonhuman primate. Murine (mouse) embryonic stem cells were isolated over 20 years ago.quot. human embryonic stem cells are attractive potential tools for gene therapy. such as neurons. embryonic stem cells were differentiated into hematopoietic quot. they retain the ability to form any cell type in the body.
However. integrates randomly into host chromosomal DNA. several copies of the therapeutic . All of these techniques have been applied to various stem cells. The levels of immune system reconstitution observed in the mice were quite modest (<1% of normal). However. since this process can induce mutations that lead to malignant transformation or serious gene dysfunction. this approach may be employed for treating human patients with immunodeficiency or other diseases that may be corrected by cell transplantation. in vitro drug selection strategies allow the isolation and expansion of cells that are stably transfected. whereas others (lentiviruses) do not require actively dividing cells. However. there are usually limitations in the size of the introduced gene. and in rare cases. Transfection utilizes chemical or physical methods to introduce new genes into cells. such as liposomes. This methodology involved using a more severely immunodeficient mouse as a recipient (which also had the murine equivalent of the human X-linked SCID mutation) and genetically engineering the hematopoietic engrafting cells with a potential oncogene prior to transplantation. Brief electric shocks are additionally used to facilitate DNA entry into living cells. by nature. In most cells. Transduction utilizes viral vectors for DNA transfer. In most cases. significant advances must first be made.16 To acquire optimal cellular material from clinical samples in larger quantities for experimental and optimization purposes is usually rather difficult since access to these samples is limited. Genes may be introduced into cells by transfection or transduction. including human embryonic stem cells. Engineered viruses can be used to introduce almost any genetic information into cells. Interestingly. the genetic information carried by the viral vector is stably integrated into the host cell genome (the total complement of chromosomes in the cell). introduce DNA or RNA into cells very efficiently. Such quot. Genetic Manipulation of Stem Cells The therapeutic gene needs to be introduced into the cell type used for therapy. including presumably tissue-specific stem cells. as well as other cationic-lipid based particles are employed to facilitate the entry of DNA encoding the gene of interest into the cells. some viruses (particularly retroviruses) only infect dividing cells effectively. the immune function in these animals was partially restored. small molecules. Usually. they may provide a constant in vitro source of cellular material. the destiny of the introduced DNA is relatively poorly controlled using these procedures. Additionally. Embryonic stem cells may additionally be indirectly beneficial for cellular gene therapy. Viruses. However.adultquot. as long as they significantly express the newly introduced gene. the DNA disappears after days or weeks.immunodeficient mice. In principle. Since these cells can be differentiated in vitro into many cell types. stem cells derived from embryonic stem cells may thus be utilized to optimize protocols for propagation and genetic manipulation techniques. An important parameter that must be carefully monitored is the random integration into the host genome. while the methodology employed to achieve hematopoietic engraftment is not clinically feasible.
gene may also be integrated into the genome. Cells that randomly incorporate recombinant DNA usually retain the entire DNA construct. and has been used extensively with mouse embryonic stem cells to investigate gene function and create mouse models of human diseases. gene silencing and positional effects were a particular problem in mouse hematopoietic stem cells.21 Homologous recombination provides a precise mechanism for defined modifications of genomes in living cells. a status denoted quot. Recombinant DNA is altered in vitro. Gene silencing refers to the phenomenon whereby over time. Next. antibiotic resistance only reveals that the cells have taken up recombinant DNA and incorporated it somewhere in the genome. including human embryonic stem cells. an exchange of homologous DNA sequences is involved. However. Cells expressing the thymidine kinase gene are killed by the antiviral drug ganciclovir in a process known as negative selection. resulting in more robust expression in differentiating cell systems. episomal systems have been applied to embryonic stem cells.. a mechanism that is not currently well understood.episomalquot. allowing cells that have incorporated the recombinant DNA to be positively selected in culture. the foreign transgene does not integrate at a high rate and remains separate from the host genomic DNA. In the past. .19 An elegant way to circumvent positional effects and gene silencing is to introduce the gene of interest specifically into a defined region of the genome by the gene targeting technique referred to previously. Specific proteins stabilizing these episomal DNA molecules have been identified as well as viruses (adenovirus) that persist stably for some time in an episomal condition. most artificially introduced active genes are turned off by the host cell. Homologous recombination is a very rare event in cells. including the herpes virus thymidine kinase gene. the end of the recombination construct often includes the thymidine kinase gene from the herpes simplex virus. helping to bypass positional effects and gene silencing. integration of several copies may help to achieve stable gene expression. To select for cells in which homologous recombination has occurred. and the non-homologous thymidine kinase gene at the end of the construct is eliminated. In cells that display homologous recombination between the recombinant construct and cellular DNA.17 These problems led to the optimization of retroviral and lentiviral vector systems by the addition of genetic control elements (referred to as chromatin domain insulators and scaffold/matrix attachment regions) into the vectors. and thus a powerful selection strategy is necessary to identify the cells in which it occurs.18 In some gene transfer systems. This in turn results in the replacement of normal genomic DNA with recombinant DNA containing genetic modifications. In these cases.20 The gene targeting technique takes advantage of a cellular DNA repair process known as homologous recombination. where it recombines with the homologous part of the cell genome. recombinant DNA is introduced by transfection into the cell. and the therapeutic gene is introduced into a copy of the genomic DNA that is targeted during this process. since a subset of the introduced genes may integrate into favorable sites. the introduced construct has an additional gene coding for antibiotic resistance (referred to as a selectable marker). Positional effects are caused by certain areas within the genome and directly influence the activity of the introduced gene. Recently. Usually.
Future Challenges for Stem Cell–Based Gene Therapy Despite promising scientific results with genetically modified stem cells. those cells undergoing homologous recombination are unique in that they are resistant to both the antibiotic and ganciclovir. and these may occur more frequently when the cells are passaged as bulk populations. and to monitor the existing . sporadic chromosomal abnormalities in human embryonic stem cell culture have been reported. The more specific and extensive the genetic modification.Therefore. and adding defined markers that allow the identification of transplanted cells. This also significantly reduces the risk of insertional mutagenesis. the cells may accumulate genetic and epigenetic changes that might harm the patient (epigenetic changes regulate gene activity without altering the genetic blueprint of the cell). For therapeutic applications in transplantation medicine. Gene targeting by homologous recombination has recently been applied to human embryonic stem cells. Indeed. allowing effective selection with these drugs (see Figure 4. This observation reinforces the necessity to optimize culture conditions further. the controlled modification of specific genes should be useful for purifying specific embryonic stem cell-derived. altering the antigenicity of embryonic stem cell derivatives. differentiated cell types from a mixed population. to explore new human embryonic stem cell lines. since the therapeutic gene can now be introduced into defined regions of the human genome.22 This is important for studying gene functions in vitro for lineage selection and marking. Although human embryonic stem cells in the culture dish remain remarkably stable. Figure 4.2). the longer the stem cells have to remain in vitro. Additionally. Gene targeting by homologous recombination.2. some major problems remain to be overcome. better controlled expression of the therapeutic gene should be possible.
25 This may be achieved by rigorous purification of embryonic stem cell derivatives or introducing suicide genes that can be externally controlled. and currently. nuclear transfer technology has been recently extended to human embryonic stem cells. If stem cells are not autologous. potentially trigger immune system responses. Safety precautions are therefore necessary. including an individual with an immunodeficiency disease. as well as vectors introducing these genes (such as those derived from viruses). Strategies to circumvent these problems.25 In this context.cell lines. immune-matched human embryonic stem cells have now been established from patients. Another issue is the patient's immune system response. such as the expression of immune system-modulating genes by stem cells. protocols are being developed to allow the complete depletion of any remaining undifferentiated embryonic stem cells. Transgenic genes. creation of chimeric.27* Strategies that combine gene targeting with embryonic stem cell-based therapy are thus potential novel therapeutic options.23.26* Notably. . immunotolerable bone marrow or suppression of HLA genes have been suggested. they eventually cause immuno-rejection of the transplanted cell type.24 Additionally undifferentiated embryonic stem cells have the potential to form a type of cancer called a teratocarcinoma. congenital hypogammaglobulinemia.
3.3). For heart failure. reverse apoptopic mechanisms and reactivate dormant cell processes will be useful. Strategies for Delivering Therapeutic Transgenes into Patients. Further research is essential to determine the full potential of both adult and embryonic stem cells in this exciting new field. According to Patel. . a cell that reduces myocardial necrosis and augments vascular blood flow will be desirable. © 2006 Terese Winslow The addition of human embryonic stem cells to the experimental gene therapy arsenal offers great promise in overcoming many of the existing problems of cellular based gene therapy that have been encountered in clinic trials (see Figure 4. suitable sources of cells for cardiac transplant will depend on the types of diseases to be treated. cells that replace or promote myogenesis. For acute myocardial infarction.Figure 4. special editor for this issue.
a process by which channels are created in heart tissues by laser or other means. Patel. The researchers speculated that there was an increase in local production of growth factors that may have improved the survival of transplanted cells. but also of timing.” Patel and colleagues. “TMR may act synergistically with signaling factors to have a more potent effect on myocardial remodeling. “Preclinical data suggests that there is a dose-dependent improvement in function. “Our study suggests that the prolongation of SDF-1 expression at the time of an acute myocardial infarction (AMI) leads to the recruitment of what may be an endogenous stem cell in the heart.” says Marc Penn. Also. Transmyocardial revasularization (TMR). Given the poor vascular supply after a heart attack and an active inflammatory process.” said Amit N. grafted cells survive with difficulty. Stem cells depolarize Recent studies have suggested that there are stem cells in the heart. a chemokine. However. who used a novel delivery system to disperse cells in the TMRgenerated channels in an animal model. “We hypothesized that using TMR as a scar pretreatment to cell therapy might improve the microenvironment to enhance cell retention and long-term graft success.” .” Will cells home to the site of injury? Labeling stem cells with durable markers will be necessary and new tracking markers may need to be developed.” Patel notes that the availability of autologous (patient self-donated) cells may fall short. Determining optimal delivery methods raise issues not only of dose. PhD.“Very little data is available to guide cell dosing in clinical studies. the poor survival of grafted cells has been a concern of researchers. In this study. “These cells may contribute to increased contractile function even in their immature stage. assessing the fate of injected cells is “critical to understanding mechanisms of action. researchers engineered mesenchymal stem cells (MSC) to over express stromal cellderived factor-1 (SDF-1). Improved cell survival drugs Adult bone marrow-derived mensenchymal stem cells (MSCs) have shown great signaling and regenerative properties when delivered to heart tissues following a myocardial infarction (MI). MD. can enhance oxygenated blood supply. lead author of a study titled Improved Cell Survival in Infarcted Myocardium Using a Novel Combination Transmyocardial Laser and Cell Delivery System.” says Patel. report significant cell survival in the TMR+Cell group versus Cells or TMR alone. director of the Skirball Laboratory for Cardiovascular Cellular Therapeutics at the Cleveland Clinic Foundation.
Our clinic offers advanced patented methods of stem cell treatment for different diseases and conditions. the favorable effects may be attributed to several mechanisms. Stem cell therapy has proven to be effective for organs and tissues restoration.” explains Chachques. cardiac cell transplantation has had limited success because of poor graft viability and low cell retention. Fetal stem cells have huge potential for differentiation and proliferation and are not rejected by the recipient’s body more.In the study titled SDF-1 Recruits Cardiac Stem Cell Like Cells that Depolarize in Vivo.” concluded Chachques. MD. embryonic stem cells. . lead author for Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Clinical Trial): One year follow-up. circulating blood-derived progenitor cells. Those cell types include skeletal myoblasts. The BMC seeded in the collagen matrix may be incorporated into the myocardium through epicardial channels created at the injection sites. a matrix seeded with bone marrow cells (BMC) was grafted onto the infarcted ventricle to help support and regenerate postischemic lesions. endothelial and mesothelial cells. potentially. We treat patients with various diseases. The outcome of this inefficient repair can have a significant impact on the electrical and mechanical functions of the surviving myocardium. adipose tissue stem cells and. The fetal stem cells we use are nonspecialized cells able to differentiate (turn) into any other cell types forming different tissues and organs. Grafting bioartifical myocardium for myocardial assistance While the object of cell transplantation is to improve ventricular function. and for fight against the incurable and obstinate diseases. limited post-ischemic remodeling and improved diastolic function. “The use of the biomaterial appears to create a micro atmosphere where both exogenous and endogenous cells find an optimal microenvironment to repair tissues and maintain low scar production.. “Our study demonstrated that bone marrow cell therapy associated with the surgical implantation onto the epicardium of a cell-seeded collagen type 1 matrix prevented myocardial wall thinning. the cell-seeded matrix may help prevent apoptosis. bone marrow-derived mensenchymal stem cells. Pompidou Hospital. “This biological approach is attractive because of its potential for aiding myocardial regeneration with a variety of cell types. Too. According to Chachques. PhD. researchers concluded that there is a natural but inefficient stem cell-based repair process following an AMI that can be manipulated through the expression of key molecular pathways.” says Juan Chachques. In a study carried out by a team of researchers from the Department of Cardiovascular Surgery..
She had asked Mr. Senthil Kumar. Senthil Kumar and his wife to consider another pregnancy and go for umbilical cord blood stem cell banking. multiple sclerosis. had recommended her to start on iron reducing medication initially. for financial assistance. cord blood stem cells free of cost at their center in Chennai. Today. Our stem cell treatments helped to prolong life and improve life quality to thousands of patients including those suffering from the incurable diseases who lost any hope for recovery.such as diabetes mellitus. If left untreated.. Thalassemia is among the most common genetic diseases worldwide. Revathy Raj who examined Thamirabharuni. The diseased person has to undergo monthly blood transfusion. We approached various societies and LifeCell International. cancer. LifeCell helped us to preserve my son’s Pugazhendhi. doctors. The first step was to destroy all the existing bone marrow cells for which chemotherapy was used. the protein in red blood cells that carries oxygen. with the guidance of the Doctors and with the aid of LifeCell International. Dr. Russian Federation. Germany.” says Mr. and 50% chance for a partial match.Thamirabharuni’s father.my friends. A newborn sibling’s umbilical cord blood provides a better chance of HLA matching as there is a 25% chance for a perfect match. severe anemia can result in insufficient growth and development. Among our patients there are also people willing to undergo anti-aging treatment. Parkinson’s disease. Thalassemia is a blood disorder passed down through families (inherited) in which the body makes an abnormal form of hameoglobin. well wishers.000 transplantations of fetal stem cells to people from many countries. bearing the medical expenses was really difficult for us. Duchenne muscular dystrophy. “I came to know about my daughter’s condition when she was one-and-half-years old. With a pre-natal test it was also confirmed that the foetus was not affected with Thalassemia. we have performed more than 6. Stem cell treatment allows for achieving effects that are far beyond the capacity of any other modern method more. China. HLA test was done which proved that the tissues of both the children matched and the treatment could proceed. as well as other common physical complications that can lead to a dramatically decreased life-expectancy. including rare genetic and hereditary diseases. the extracted cord blood stem cells were preserved under specific conditions. Also using a sibling’s cord blood for transplant lowers the chances of donor rejection. Poland. Greece and Cyprus.. The disorder results in excessive destruction of red blood cells and causes severe anemia that can occur within months after birth. I would like to thank all the kind souls. Being a carpenter by profession. Pugazhendhi has become a means for his sister’s survival from Thalassemia. For a year. etc. For over 17 years. Italy. and is therefore considered as a preferred source for transplantation compared to using stem cells from a non-related source. blood diseases and many others. Then the donor’s stem cells were injected in the . such as the USA. anonymous donors who helped and guided me at different stages.
the world’s largest and oldest stem cell bank with more than 16 years of expertise in stem cell banking. the stem cells transplantation was done by Dr.patient body.000 children with Thalassemia major are born in India. Revathy Raj at the Apollo Hospital and it helped Thamirabharuni get rid of Thalassemia.Menstrual Blood Stem Cell Banking. Mayur Abhaya. LifeCell facilitates the cryogenic preservation of stem cells in technological collaboration with Cryo-Cell International Inc. LifeCell International says. About LifeCell International: LifeCell is India’s first & largest umbilical cord blood stem cell bank to bring the revolutionary concept of banking a baby’s umbilical cord blood stem to the country. Today LifeCell has over thousands of members who have preserved their baby’s cord blood stem cells and has over 50 centers across India and abroad. The procedure requires no surgery! explains Dr Revathy Raj. Govt. Clinical Trials and Stem Cell Therapy. With addition of this service LifeCell will become the first & only comprehensive stem cells solutions provider in the world to offer a complete spectrum of services in stem cells through multi-service banking. of India for R&D.. which constitutes 10% of the total number in the world. When they used the needles for blood transfusion it would hurt… and sometimes they would never get the vein but still I had to go for blood transfusion every month. Senthil Kumar and his family on Thamirabharuni’s triumph over Thalassemia. It feels very fulfilling that LifeCell could make an impact in a child’s life… we are very happy to be a part of this success story. The company will soon be launching another revolutionary service in Stem Cell Banking . R&D. This success I am sure will give new hope to thousands of families whose children are unfortunately the victim of this dreadful disease. In March 2009.” Every year 10. for every woman to preserve her stem cells and potentially secure her future from lifethreatening diseases. several life threatening diseases like Thalassemia. and one out of every 8 carriers of Thalassemia worldwide lives in India . I love my brother. Says Thamirabharuni. Leukaemia etc. “We at LifeCell would like to congratulate Mr. LifeCell in the past 4 years has positioned itself as leaders in the Industry and was recently accredited by AABB (American Association of Blood Banks) for adopting their international standards and today LifeCell is the “First AABB Accredited Stem Cell Bank in India” and recognized by DSIR. . can now be treated completely with no surgery involved. The stem cells that were transplanted came from her brother’s cord blood and his bone marrow as there was deficient amount of stem cells in Pugazhendhi cord blood. Mr. My Brother’s cord blood saved me or I knew I wouldn’t have been alive for long. USA . President and Executive Director.Thanks to this revolutionary development in the stem cell industry.