Brave New World of the clone and stem cell
By James Horsley
Published: February 23, 2010
Editor's note: This series is intended as an exposé of the embryonic stem cell research industry. It is the opinion of this author that the highly educated research scientists in regenerative medicine are using their level of learning to pull the wool over the eyes of the general public by advancing the advantages of stem cell research as a cure for numerous diseases and injuries, clocking in technical language the fact that their research is taking the lives of human beings and to date has provided no cures. This article is a series of three that will attempt to demystify stem cell research.
There are three chapters to Part I of this series of about 10 pages each.
| Chapter 2. | Chapter 3. |
Dr. Shinya Yamanaka, while peering through a microscope at a friend's fertility clinic, saw what he thought could have easily been one of his own daughters.
When he made the social call, Dr. Yamanaka was an assistant professor of pharmacology, researching embryonic stem cells. At his friend's invitation he looked down the microscope at one of the human embryos stored at the clinic. What he viewed changed his scientific career.
"When I saw the embryo, I suddenly realized there was such a small difference between it and my daughters," he said. "I thought, we can't keep destroying embryos for our research. There must be another way."
After years of searching, Dr. Yamanaka, 45, a father of two and now a professor at the Institute for Integrated Cell-Material Sciences at Kyoto University, Japan, may have found "another way."
Dr. Yamanaka's research group in 2007 was one of two that independently announced they had successfully turned adult skin cells into the equivalent of human embryonic stem cells (hESC) without using an actual embryo. The other group was led by James A. Thomson at the University of Wisconsin, one of the first scientists to isolate human embryonic stem cells (Fackler, 2007).
The announcement was hailed as a scientific and ethical breakthrough, as it was touted as avoiding the destruction of human embryos for research and medical purposes.
But, in the end, does it? Let us look at the issue more closely.
Human embryonic stem cells have the potential of curing diseases, because they are capable of differentiating into all the 210 distinct types of cells composing the body, such as brain, nerves, bone, heart, liver, kidneys and fingernails. Because of this ability to turn into different types of tissue, stem cells are being investigated as possible cures of disease and as possible means to repair injured or diseased organs, such as a heart or a spinal cord.
Theoretically, such cells could be modified in the laboratory to cure a patient of a disease, such as Parkinson's Disease, or to produce tissue or an organ to replace a patient's defective one. However, stem cells from an embryo normally have a genetic structure of another, distinct person. They are not copies of the patient's DNA. Such cells, when transplanted, will stimulate the patient's immune response and would be destroyed. This is because such new cells are identified by the patient's body as being foreign, triggering the same immune response responsible for killing invading bacteria.
Prior to this discovery, one method of obtaining stem cells that in theory would not be rejected was by a process called somatic cell nuclear transfer (SCNT), a method first used to clone Dolly the sheep. This process produces clones of cells that have the same genetic structure as the donor. The donor could be the patient himself.
SCNT takes the nucleus, or the stem cells, from an embryo and replaces them with skin cells from the donor. The embryo's outer wall, the trophoblast, for reasons as yet unknown, converts these skins cells back to stem cells. If allowed to grow, they will produce a clone of the donor, resulting in tissue that could be used for transplantation that would not be rejected, having the same DNA as the patient. But, to get these cells, an embryo initially must be destroyed.
At the human level, although viewed as having a potential to benefit mankind, stem cell research from its inception has been embroiled in controversy, with many questing its morality, since stem cells, when extracted from an embryo, prevent it from becoming a living organism, that is, a person.
By Yamanaka's methods, laboratory-created stem cells, called "induced pluripotency stem cells" or iPS cells, are produced by a procedure called "cell regression." Skin cells are turned into embryonic-like stem cells by using viruses, instead of an embryo. The method does this by carrying genes into the skin cell, reprogramming its genetic structure to that of a stem cell. In essence, the process sets back its genetic clock, making it a more primitive, all purpose cell, that is, a stem cell.
Because iPS cells have all the properties of embryonic stem cells, but are obtained from skin tissue without using embryos, this development was lauded by numerous pro-life groups, religious organizations and even former President George Bush, himself. Here is what a few said on its announcement in the press:
On learning of the breakthrough, President Bush said he was pleased to learn that scientists have reprogrammed skin cells into stem cells "within ethical boundaries."
Others echoed his praise of the procedure.
"Once again science is catching up to ethics, proving that the moral way is the most sound, scientific choice. This breakthrough allows scientists to further their research and continue to develop medical advances while still honoring the sanctity of life," said Wendy Wright, President of Concerned Women for America. "Policymakers can safely abandon the politically-charged demand to fund the destruction of embryos to find stem cell solutions."
But, again, is this really the case? Does iPS technology avoid violating the sanctity of life at all levels of stem cell research? And, can policymakers give up the fight to stop the federal and state funding of stem cell research because of the iPS breakthrough?
The answer is no.Where is biological engineering leading us?
To understand why, one must have an understanding of the complexities facing researchers as they try to derive medical benefits from stem cells.
Stem cells are pluripotent. Pluripotency means that the cells have the potential of developing into any one of the 210 cell-types in the human body, but that they are not totipotent, that is, they can not go the next step and become a human creature. This is because these cells are not the entire embryo, just the inside cell mass. They lack the ability to develop a placenta. This lack means they can not attach to the womb to receive nurshiment and will die.
To put it another way, while pluripotent stem cells have the potential of developing into different specialized cells, without the trophoblast, the embryonic outer shell, they can not differentiate spontaneously. Without that capability, they can not become nerves, hands, a heart or a brain, and thus can not develop into a human being or any of a human being's parts via natural means, that is, by a pregnancy.
What researchers are trying to do is find some way to achieve differentiation into various bodily parts in a laboratory, circumventing pregnancy and on top of that, without the aid of the embryonic outer wall, the all-important trophoblast. Such a goal requires a great deal of hubris, akin to trying to grow a rose bud in a laboratory without growing the bush first. The goal of the regenerative scientists may be logically, structurally and chemically impossible. To obtain bodily parts, one may have to grow a human being first. Life may be something that must be achieved by developing it as a unit, instead of part by part.
Unable to accomplish differentiation in the laboratory from stem cells alone to date, some researchers are turning to a process less daunting, attempting to use the entire embryo to achieve differentiation, implanting stem cells into an egg, creating an embryo, then extracting the partially differentiated stem cells for research purposes, thereby killing that embryo. This is cloning, often called "therapeutic cloning." While theoretically less challenging, despite numerous research programs to achieve this end, no human being has to date been cloned beyond the blastocyst stage.
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On the right is the natural development of cells from the blastocyst, the embryo, into specific cells, like heart and nerve cells, which together produce a human being. On the left, cells have been scooped out of the blastocyst and are cultured in a Patri dish. Researchers are attempting to go from cultured pluripotent stem cells to tissue specific cells, skipping the natural growth of the blastocyst that occurs in the womb. |
Stem cells in a dish
Let us look at the state of stem cell research in more detail and how iPS technology fits in. Scientists can grow stem cells in Petri dishes, that is, laboratory dishes for medical studies. IPS technology is regarded as important because a major objective of researchers is to obtain stem cells that have the potential of developing into tissue or organs that will not be rejected due to a patient's immune response. Since iPS cells produce exact copies of a person's DNA, they could, in theory, produce tissue or organs that would not be rejected by the body's immune response.
At present, organs or tissue, such as a heart, when transplanted using conventional surgical methods into a patient from a donor--say, the heart of a person who has been killed in an automobile wreck--requires the administration of immunosuppressive drugs to the transplant patient, as a heart from another person is viewed by the patient's body as a foreign substance and is destroyed, just as the body destroys bacteria.
However, immunosuppressive drugs that curb rejection, leave the body vulnerable to infection and is the major drawback to conventional organ transplantation. Such drugs can lead to death of the recipient from cardiovascular disease, infection, and cancer (Dantal, et al, 2005).
One of the hopes of regenerative medicine is to develop a stem cell line of patient-specific stem cells, that is, colonies of stem cells that are copies of the patient's DNA. Such stem cell lines could be experimented on, using various drugs and gene therapies, to modify and correct diseased or injured tissue from patients. These modified tissues or organs could then conceivably be transplanted back into a patient to produce a cure of a specific disease or to replace a defective or injured organ. (Stem Cell Basics, 2009).
In fact, researchers from the Harvard Stem Cell Institute (HSCI) at Harvard and Children's Hospital Boston have begun experiments using somatic cell nuclear transfer, i.e., cloning, to create disease-specific stem cell lines in an effort to develop medical treatments (Harvard stem cell researchers granted approval, 2006).
The project is a collaborative effort of 100 researchers, under the direction of Douglas Melton, co-director of HSCI and Assistant Professor Kevin Eggan of Harvard's Faculty of Arts and Sciences, Department of Molecular and Cellular Biology, and Harvard Medical School Associate Professor George Daley of Children's Hospital Boston.
(Melton, one of the most prominent persons in regenerative medicine, in addition to being the co-director of the Harvard Stem Cell Institute, is an investigator of the Howard Hughes Medical Institute, the Thomas Dudley Cabot Professor in the Natural Sciences of the Harvard University Faculty of Arts and Sciences, chairperson of the Harvard University Department of Stem Cell and Regenerative Biology, a faculty member of the Department of Molecular and Cellular Biology, a member of the National Academy of Science, a founding member of the International Society for Stem Cell Research, and is on the Science Advisory Board of the Genetics Policy Institute.)Daley explained that the ultimate goal, once they understand how embryonic stem cells are programmed to differentiate into specific cell types, is to literally move a patient's disease into a Petri dish. "We plan to take skin cells from a patient with a genetic disease, like sickle cell anemia or any one of more than 40 bone marrow disorders, and reprogram that skin cell back to its embryonic state. We can then study the disease using these cells, correct their genetic defects and coax the repaired cells to become normal blood cells. Our ultimate goal is to return the repaired cells to the patients."
Theoretically, such cells, genetically identical to the patients receiving them, would be accepted by the patient's immune system and wouldn't require the use of immunosuppressive drugs. But in this research study, it would come at an ethical price--the harvesting of eggs and the destruction of embryos.
But, Melton responds, "all human cells, even individual sperm and eggs, are 'living.' The relevant question is 'when does personhood begin?' That's a valid theological or philosophical question, but from the scientific perspective, this work holds enormous potential to save lives, cure diseases, and improve the health of millions of people. The reality of the suffering of those individuals far outweighs the potential of blastocysts that would never be implanted and allowed to come to term even if we did not do this research," he said.
Aside from the fact that all blastocysts, that is embryos, have the potential for life, the statement that the blastocysts they are studying could never come to term is misleading, for the researchers have collected ova from women directly for this research project for the purpose of removing the stem cells from the donor's egg and replacing them with patient donor's skin cells so as to create a clone of the patient. Commenting on the nature of the collection process, the article states:
Under the protocol approved by the Institutional Review Board (IRB) of Harvard's Faculty of Arts and Science, and the IRB of Boston IVF, ...ova will be collected for Melton and Eggan's work...
While ovum is not an embryo, once it is either fertilized by sperm or implanted with a skin cell via SCNT and then submitted to an electrical shock, the ovum becomes an embryo. The research, itself, made sure that such eggs and the resultant blastocysts could never come to term because they would not be implanted and because they had their stem cells harvested for research purposes, thereby destroying the embryo created by the researchers.
One hope of the technology that produces iPS cells is to create stem cell lines that would avoid this controversy.
Such cell lines have already been established at the Harvard Stem Cell Institute and the University of Wisconsin-Madison's WiCell Research Institute. At HSCI researchers have created iPS lines from patients with 10 different diseases, including Parkinson's Disease, Type I diabetes, Huntington's Disease, Down Syndrome, a form of combined immunodeficiency ("Bubble Boy's Disease"), and two forms of Muscular Dystrophy (Twenty Disease-Specific Stem Cell Lines Created, 2008). The WiCell Bank is offering three iPS cell lines, genetically reprogrammed from human skin cells to an embryonic state. According to Erik Forsberg, executive director of the WiCell Research Institute, "they represent the next generation of stem cell research" (Kelly, 2008).
Such cells are, as mentioned, in essence clones, but only genetically. Being pluripotent, not totipotent, they could not grow to become a person.
Does this new method destroy embryos?
In the past, to obtain stem cells, excess embryos were used from fertility clinics. However, as mentioned, the process of extracting the stem cells destroyed the embryo. So, does this new iPS technology avoid the destruction of embryonic life? The answer depends on the research application of the iPS cells.
Using stem cells, there are several theoretical ways to grow tissue or organs for regenerative purposes, such as repairing a failing heart or a damaged spinal cord, or, say, replacing an amputated finger.
As mentioned, one way is to manipulate stem cells in the laboratory, engineering them to differentiate into specific cells types, such as heart muscle or nerve tissue. A researcher either can attempt to grow such tissue in the laboratory as an isolated organ, that is, attempt to grow a live, pumping heart in a test tube-type environment or, instead, inject the modified heart muscle cells into an ailing patient's heart to repair it. And, as explained, still another way is to experiment on stem cells from individuals with certain diseases in an effort to manipulate these cells to achieve cures.
However, to date no human embryonic stem cells, nor human embryonic-like stem cells, that is iPS cells, have been successfully used to treat disease or injury. As the National Institute of Health puts it: "Although hESCs [human embryonic stem cells] are thought to offer potential cures and therapies for many devastating diseases, research using them is still in its early stages (FAQs, 2009)."
The closest science has come so far in the United States is a clinical trial by California-based Geron Corporation, launched in 2009. The goal of the trial is to restore function to patients with injured spinal cords, but no results as yet have been published. While such therapies are viewed as promising, the complexities scientists face regarding such stem cell derived cures are staggering. And the therapies studied at Geron involve embryonic stem cells, not iPS cells (Geron Receives FDA Clearance to Begin World's First Human Clinical Trial of Embryonic Stem Cell-Based Therapy, 2009).
If researchers limited their investigation to treatment of disease states by experimenting on stem cells derived from persons using skin samples to create iPS cells, no ethical considerations would be involved, for no embryo would be destroyed. However, problems emerge when investigators attempt to find ways to coax cells to differentiate into specific tissue or organs that can be transplanted. Stem cells that have not been differentiated into matching tissue usually form tumors when transplanted.
Cellular differentiation not well understood
In the growth process, various specialized parts of the body are formed as cells divide and differentiate. While cell division and differentiation are processes that are occurring at the same time, they refer to different aspects of development, Dr. Bill Todt , Jones Science Center associate professor and chair of biology at Concordia College, Moorhead, Minnesota, explained during a recent interview. "Cell division is simply causing the cell to produce more cells like itself. Differentiation is the process of cells becoming specialized to do specific tasks or to have specific fates," he said.
"Early on in the embryo, cell division is important, because in order to have cells becoming different from each other, you need lots of cells. As more and more cells are produced, then some of them can go ahead and start down their particular pathway and become different from their neighbors. That's the differentiation part," Todt said.
One method by which differentiation is achieved is by chemicals called "growth factors."
The term growth factor refers to a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes. They have the potential of directing the differentiation of stem cells into specific tissue types.
In one study, eight growth factors were applied to cultured human embryonic stem cells to observe their effects on cell differentiation by research teams led by Howard Hughes Medical Institute investigator Melton and Hebrew University geneticist Nissim Benvenisty, as reported in a research article published in the October 10, 2000 issue of Proceedings of the National Academy of Sciences.
What they found is that growth factors operate in a general way to begin with and did not directly work to achieve differentiation into specific cell types.
"When an egg cell divides, it doesn't immediately tell its daughter cells to become nerve, brain or pancreatic cells," Melton explained. "Rather, it first parses cells into the three general territories (germ layers)-ectoderm, mesoderm and endoderm. And, our studies showed that the growth factors encourage cells to develop into more of one germ layer and less of the other two."
Endodermal cells specialize into such organs as the liver and pancreas. Ectodermal cells become brain, skin and adrenal tissues. And mesodermal cells become muscle. But the research could not determine how the general category of cells became specialized. If you compared this process to building a house, the research produced a glimmer on how a building site (a germ layer) is established, but how to build a building (an organ) remained a mystery.

Ultimately, he said, controlling stem cell differentiation will likely involve a strategy that employs multiple growth factors in a certain order and at certain times.
"It may be a bit like educating a child, in which you don't designate children in kindergarten as doctors, lawyers or surgeons, but you give them some kind of general education." Melton noted. "And, as they progress and show an interest in a specific field, you give them a more specialized education."

"In the best of all possible worlds, one would like to find [that] growth factors could be added to a human embryonic stem cell to make it become a cardiomyocyte to replace defective heart muscle or a pancreatic beta cell for transplantation into diabetics," Melton said. "But these studies strongly suggest that finding such a factor will be exceedingly unlikely (Study Reveals How Growth Factors Affect Human Stem Cells, 2000)."
Trying to differentiate cells outside the environment of the embryonic walls, that is, in the laboratory, is sort of like trying to assemble a Mercedes Benz in your back yard, instead of on an assembly line, with a few tools from your garage. And no manual. And this would be a snap compared to what the stem cell research scientists are attempting to do.
| Chapter 1. | Chapter 3. |
The language of the scientists and their supporters is clinical, meliorative and humane, but it gives off an unmistakable whiff of cannibalism.
The next step: cloning
Besides modifying stem cells in the laboratory, researchers have few other alternatives. If immunological rejection is to be avoided, one of the most logically evident alternatives involves cloning.
To obtain organs or tissue for transplantation or other cures, if cloning is used, a scientist has two clonal alternatives, i.e., either "therapeutic cloning" or "reproductive cloning."
Cloning is achieved conventionally by transferring a somatic cell into an unfertilized egg through the process of somatic cell nuclear transfer.
However, one could conceivably use a stem cell or an iPS cell for the nuclear transfer, instead of a skin cell. Regardless of what method is used, to utilize the clone for medical purposes, scientists can either allow the clone to grow to a certain stage for several days, then harvest the stem cells, destroying the embryo--this is conventionally called "therapeutic cloning"--or implant the embryo into the womb of a human mother, allowing it to come to term--this is "reproductive cloning."
In reproductive cloning, such clones theoretically would grow up, and as either children or adults, have their organs harvested for medical applications, much like in "Never Let Me Go," Kazuo Ishiguro's recent and widely acclaimed novel about a young girl (a clone) coming of age on an organ farm--an English boarding school--where members were created and trained for no other purpose than to provide healthy organs for the sick and feeble.

At any level, whether therapeutic or reproductive, cloning leads eventually to a dilemma. It invites us to determine what class of beings deserve to be cured and what class of beings deserve to be bred and destroyed for their cure.
The whiff of cannibalism
In a review of "Never Let Me Go," in the November 27, 2005 New York Times, Gary Rosen, managing editor of Commentary magazine, said that while most decry reproductive cloning, therapeutic cloning is being pursued because it avoids immune rejection by drawing stem cells from embryonic clones of the patients themselves. Rosen noted:
Still, you don't have to be a raving Bible-thumper to entertain moral doubts about so-called therapeutic cloning ("therapeutic," that is, for potential patients; not such a great deal for the embryos). All you need is a bit of Kant from Ethics 101, especially the part about treating other people, presumably even proto-people, not as a means to your own ends but as ends in themselves. It is an injunction hard to square with the literature on SCNT, with its talk of "harvesting" and "programming" stem cells. The language of the scientists and their supporters is clinical, meliorative and humane, but it gives off an unmistakable whiff of cannibalism.
Cloning a primary goal
However, cloning may be regenerative medicine's best bet due to the enormous complexities involved in getting stem cells to differentiate into usable transplant tissue. In fact, therapeutic cloning, using the procedure of somatic cell nuclear transfer, is indeed a primary goal of regenerative medicine. SCNT is a stated goal by the Committee on the Biological and Biomedical Application of Stem Cell Research, the Board on Life Science, National Research Council, and the Board of Neuroscience and Behavioral Health, Institute of Medicine (Stem Cells and the future of regenerative medicine, 2002).
To more fully appreciate why cloning is so important to the goals of regenerative medicine, one must understand its biological basis and what is actually meant by such terms such as "embryo", "stem cells," "differentiate" and "clone." See: Stem cells: frequently asked questions.
Hello, Dolly
Until recently, fertilization of an egg by sperm was the only way to create an embryo. However, "Hello, Dolly."
On July 5, 1996 a lamb was born, cloned from the cells of a sheep's udder. Being cloned from part of a mammary gland, she was named "Dolly" after the famously busty country western singer Dolly Parton.
She became the first viable offspring ever derived from an adult mammalian cell, that is, a body cell, called a somatic cell, as opposed to conventional propagation from reproductive cells, called germs cells, such as egg and sperm cells (Henahan, 1997).
The procedure used was deceptively simple--the researchers removed an unfertilized egg cell from an adult ewe and replaced its nucleus, that is, its stem cells, with the nucleus of an adult sheep mammary gland cell. The nucleus contains the cell's genetic material. This modified egg was then implanted in another ewe.
For reasons that are not fully understood, the environment of the egg, which includes the trophoblast, reprogrammed the skin cell into stem cells. The outer wall of the egg surrounding the inner cells functions as a magic room, so to speak, converting the skin cells into stem cells. But its magic goes far beyond this experiment. The embryonic shell does what scientists cannot do despite spending billions of dollars. It enables stem cells to differentiate. The magic of the embryo, that is, both the stem cells and the trophoblast, working in combination produce life--a living, separate, distinct being.
In the sheep experiment, following the administration of an electrical shock, the embryo began to divide, and differentiate, eventually becoming a fetus and coming to term, producing Dolly, a copy or clone of the sheep from which the nucleus was originally extracted out of the udder cell. Both Dolly, and the donor "mother" ewe (not the ewe in which the embryo was implanted) were genetically the same, as sperm was not used for propagation, but simply cell replication.
Questions arise
But, questions begin to arise. Just what kind of a creature was Dolly? Was she any less of a sheep than the ewe from which her cell was derived? On material grounds, maybe, for she died relatively young for sheep, at the age of six, from progressive lung disease. Genetically, she was less viable than a sheep bred conventionally. But, by definition, as an animal, was she any less of a sheep, or, indeed, was she a sheep at all?
And what about the ethical considerations, when concerning possible human application? While an egg was not fertilized by sperm to create Dolly, an egg, nevertheless, was used and, in the process, destroyed by the removal of its nucleus.
An egg has the potential--having all the genetic information in the nucleus--of becoming a human being if united with sperm. Even by itself, an egg, theoretically, could be cloned using its own DNA through parthenogenesis, an asexual form of reproduction found in some female species, and possibly achievable in humans, where growth and development of embryos occurs without fertilization by a male.
However, iPS cells have the potential of avoiding these ethical dilemmas. With the discovery of iPS technology, researchers began to switch to this method for the study of stem cells.
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| An egg from which the inner mass, that is, stem cells, is being removed for cloning purposes. |
Professor Ian Wilmut, Edinburgh University, the scientist who led the team that created Dolly the sheep, recently announced that he is abandoning the cloning of human embryos in stem cell research. Instead, he will use the method developed by Dr. Yamanaka, that is, using iPs technology.
Professor Wilmut said: "We've not made this decision because it's ethically better. To me it's always been ethically acceptable to think that if you could use cells from a human embryo to develop a treatment for a disease like motor neurone disease, for which there is no treatment at present, then that is an acceptable thing to do (Dolly scientist abandons cloning, 2007)."
Instead, he said, it was being used for practical purposes, although he mentioned, that the Japanese approach is also "easier to accept socially (Lavin, 2007)."
So, in the mind of researchers such as Wilmut, embryos and the clones derived from them have less standing than conventionally born individuals. Such researchers do not believe it is unethical to sacrifice embryonic and clonal life for the benefit of privileged others. This is an ethical view that literally values an "eye for an eye and a tooth for a tooth"--not as punishment, but as a cure. However, the cure is punishing for the embryo or the clone. It is a death sentence.
Future of embryonic stem cell research
Without taking the step into cloning and using stem cells alone, where will this take us? That is, just how far can scientists get in their goals to achieve therapies? Let us look at some of the efforts.
Researchers at the Technion-Israel Institute of Technology, Haifa, have given us a clue as to what direction they must go and what obstacles must be overcome. They have created new heart muscle with its own blood supply using human embryonic stem cells. The researchers say the newly engineered muscle could replace cardiac tissue damaged in heart attacks. Their study was published online January 11, 2007, in the journal Circulation Research (Beating Heart Muscle With Built-In Blood Supply Created From Stem Cells, 2007).
This is the first time that three-dimensional human cardiac tissue complete with blood vessels has been constructed, according to Professor Shulamit Levenberg of the Technion Biomedical Engineering Department and Professor Lior Gepstein of the Faculty of Medicine.
The researchers engineered the heart muscle by seeding a sponge-like, three-dimensional plastic scaffold with heart muscle cells and blood vessel cells produced by human embryonic stem cells, along with cells called embryonic fibroblasts.
Levenberg's research team used a similar technique in 2005 to grow skeletal muscle from scratch, and she says the lessons learned from that study helped in designing the heart muscle. For instance, the skeletal muscle study showed that it was important to grow all the different cell types together on the scaffold, and that fibroblasts were key to supporting the blood vessel walls as they developed (Ritter, 2009).
But this method, so far, has not reached the state where it can be used to treat heart disease. So far, generation of nerve tissue from stem cells have shown the most promise. But whole organ replacement from embryonic stem cells alone is thought by many to be unachievable.
The world's first tissue-engineered whole organ transplant--using a windpipe made with the patient's own stem cells--was carried out recently by surgeons from Spain. However, these stem cells were not embryonic stem cells. Instead, two types of cells were used--cells lining the patient's windpipe, and adult stem cells, very immature cells from the bone marrow, which were encouraged to grow into the cells that normally surround the windpipe (Roberts, 2008).
Induction
Adult stem cells have gone through a partial differentiation process. But embryonic stem cells must start from scratch. Why does this difference between adult stem cells and embryonic stem cells present such a barrier regarding embryonic stem cells when trying to coak them into developing into different types of cells?
As Dr. Todt explained, the growth from embryonic stem cells to a fully developed organism, such as a person, depends first on having a great number of cells and then on having those cells become specialized into various parts of the body. A cell's DNA stores the genetic instructions used in the development and functioning of all known living organisms. But, since all cells in each individual contain the exact same information as its neighbors, having the same DNA specific to that person, how do these cells become different form its neighbor? How do the cells containing the same information develop into diferent kinds of cells, say a heart cell or a nerve cell?
It depends in part on what is called "gene expression." Like books in a library, the purpose of genes is to store information. Each gene is a book containing the information required to make a protein, the building blocks of a cell. In the same way that books may be taken off a shelf and read, genes are selectively read and transcribed or "expressed" to produce the protein molecules in every cell. What books are read and how they are read govern what characteristics a cell will possess. (Twyman, 2003). But how does this system produce proteins that know what kind of cell to be, say a heart cell, and where to go in the body?
As the cells begin to form the ball of a blastocyst and progress into various stages, the mass begins to flatten and fold in on itself. As this growth transpires, cells begin to understand what they are, where they are and what their mission is by the process called "induction." As the experiments above indicate, a scaffold is often necessary to even begin to grow something like a heart. This is in part because cells grow and differentiate by sensing position.
Induction is the influence of one cell group over a neighboring cell group. Roughly speaking, cells during embryonic growth develop much like a blind person trying to set a table. As a blind person might touch a plate to see where the knife, fork and spoon goes, so cells grow and differentiate by sensing their position. For instance, the lens of an eye folds in on itself, giving rise to the optic cup and eventually the retina by the process of induction. It is thought that possibly chemicals on the surface of a cell possess the sensing information that controls this growth, producing signals that activate genes in still other cells (Mader, 2000). The necessary "scaffold" may be the growing body itself.
Mission impossible?
Recall that stem cells cannot grow into a human being without the presence of the embryo and its outer shell, the trophoblast. All they can do is multiply in a Petri dish, replicating themselves without end and without differentiation. What scientists are trying to do is mimic what an embryo does--without using an embryo, which includes both the stem cells and the trophoblast. They are trying to find the chemicals and their sequences of application that control the processes of differentiation and induction, attempting to build, for instance, a replica of a heart with cells on an artificial scaffold. In sum, a goal of whole organ regenerative medicine is to grow a heart without growing a complete human body.
However, this research may be like trying to build an elevator without first erecting a building, or just building the top floor of a skyscraper, without the intervening floors, or, as initially mentioned, growing a rose bud without first growing a rose bush. It may be a mission that is logically and structurally impossible. It may be that to grow the heart or brain or skeleton of a body, you may have to grow the entire body. It may be that you cannot short-cut this process by simply growing a heart in a test tube. A Petri dish or a test tube or even an artificial scaffold may not provide the positional cues to enable a cell to become a specialized heart cell.
What to do?
So, what is a poor scientist to do? The solution is logically obvious--use the best manufacturing plant around--the embryo, that is, both the stem cells and the trophoblast. And in so doing, we are back to square one, for at some point an embryo, or a fetus, or a fully developed human being will be destroyed, regardless of whether we use SCNT or iPS or whatever.
As reported in interview by Scientific American July 22, 2008, Dr. Wilmut, the creator of Dolly, agreed there was increasing sentiment among scientists that some form of reproductive cloning would be acceptable for clinical purposes. He said:
Suppose it was possible to use this technique to correct a genetic error in an embryo? You know, say, if you had a family who were inheriting one of the diseases we've already talked about. If you produced an embryo by in vitro fertilization (IVF), grew out cells, corrected the mutation, and then cloned to make a new embryo, you're using it as a tool for correction of genetic disease--and that child would not be a genetically identical twin. I personally wouldn't find anything wrong with that. Whether it's likely to happen or not is a very different matter, simply because of the technical challenges and the costs involved.
The process would involve removing the stem cells from an embryo, changing the genetic structure, then putting the cells into another egg, creating another being. This, in essence is producing "designer children." Being that this new child would not be identical genetically, such reproduction would at the price of destroying another life.
Someday, we might read advertisements like this:
Egg Donors Needed. $10,000. Seek women who are attractive, under the age of 29 and have SAT scores above 1,300.
Someday? That someday is now.
Ads like this routinely appear in newspapers on college campuses and in Craigslist. The one above appeared in The Daily Californian, Berkeley, placed by a San Diego broker called A Perfect Match, trying to find an egg donor whose eggs would be fertilized by the husband of a women who could not ovulate, then implanted in her, his wife, achieving pregnancy. The child would be a genetic combination of the donor and the husband, but not the husband's wife, who would carry the child to term.
Such egg "donors" are being paid thousands for the retrieval and use of their eggs. "Donor," while it is the term being used, is a misnomer because compensation is involved.
For sample advertisements see: Egg Donors Needed - $5500/donation! and Egg Donors Needed for Stay at Home Mom Income.
Stem-cell research could spur egg-donor demand, such as California's $3 billion embryonic stem-cell research program. While scientists mostly work with unused embryos stored at fertility clinics, for the newest research, they need unfertilized eggs. As explained in USA Today, scientists are involved with research that removes the egg's DNA, destroying the egg's original stem cells, then replacing it with DNA, that is, stem cells from another donor. The resultant embryo is allowed to grow, then after several days of growth in the laboratory, it, too, is destroyed when the stem cells are harvested for further research (Hopkins, 2006).
While federal funding of stem cell research is limited to certain existing stem cell lines, "there is no federal law banning human cloning altogether," according to the National Conference of State Legislatures. State laws on cloning vary widely, with some prohibiting research on cloned embryos, such as North Dakota, and other with no restrictions, such as Connecticut. Some states allow cloning, but prohibit the sale of embroys, such as California (Stem Cell Research, 2008).
Several California universities have indicated their interest in creating stem-cell lines with cloned human embryos, and for that, they'll need egg donors. They even have classes for prospective egg donors. The Institute of Medicine and the California agency that will distribute the $3 billion approved for stem-cell research in California, on November 19, 2009, sponsored a workshop on what is known about the risks of egg donation. In addition, California Gov. Arnold Schwarzenegger on September 28, 2006 signed into law a bill extending protections for women who donate their eggs for research, such as provisions for informed consent and outlining what are the potential risks of the procedure. (Palca and Block, 2009).
Can you grow a heart without a body?
But, why stop here? Why stop at therapeutic cloning? (And the terms therapeutic cloning and reproductive cloning begin to blend, for really all cloning is reproductive.) Why not will opt for letting the embryo grow to a more advanced stage to get heart cells.
Leaving ethical concerns behind, maybe the scientifically viable solution would be to allow the embryonic stem cells to grow inside the embryonic shell, instead of extracting them and throwing the shell away. Why not implant the modified embryo in a human mother? When sufficiently developed, harvest the embryo or fetus and obtain the required organ, whether it be a heart or a hand. It could mean growing clones of oneself, and others, to eventually serve as organ donors.
The only problem is that at the embryonic or fetal stage, the heart is too small to pump sufficient blood if it were grafted into an adult patient's body. Time is needed to grow a large enough heart. So, why stop at the embryonic stage? Why stop at the fetal stage?
Following implantation, just allow the clonal embryo to grow inside the womb, that is, let the embryo develop inside a mother, grow to term, and then be harvested at a size sufficient to produce a big enough heart--maybe at the child stage or young adult stage. The only problem is that "stage" is a person.
Given sufficient technological advances, what can logically be conceived by science, in the absence of morals and laws, could be done.
| Chapter 1. | Chapter 2. |
"I saw the dull yellow eye of the creature open; it breathed hard, and a convulsive motion agitated its limbs." from Frankenstein or The Modern Prometheus
On the way to Frankenstein
But, where does this lead us? It could lead us to Frankenstein.
In a report aired January 17, 2008. by NBC chief scientific correspondent Robert Bazell, Dr. Samuel Wood of Stemagen Corporation--a privately held embryonic stem cell research company in La Jolla, California--related an experience similar to the one Dr. Yamanaka had in looking down a microscope at an embryo (Bazell, 2008).
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But instead of seeing what might be the embryo of one of his daughters, he saw his own embryo. As reported in the journal Stem Cell, Dr. Wood had cloned...himself.
Using material from his own skin, he inserted the nucleus into a human egg by means of nuclear transfer, creating stem cells inside the egg with his own DNA. He then placed it in a Petri dish and allowed it to divide, reaching the blastocyst or early embryonic stage. A research colleague also did the same thing.
"It was an amazing experience to look at that blastocyst and realize that it came from one of my cells," Dr. Wood said. "It's a bit like looking at yourself from a long time ago."
Indeed, that "long time ago" being shortly after his own conception.
As the MSNBC interviewer Bazell commented, "it is the first instance of cloning humans--only as embryos in a Petri dish, but still cloned human beings." Dr. Wood and his colleague destroyed the embryos and they did not develop into a stem cell line.
The experiment by the Stemagen Corporation demonstrated that a human clone can be created from skin cells, enabling science to create an exact copy of a patient's own stem cells, that is, a clone of a patient, having his own particular DNA, avoiding immunological rejection of organs derived from that clone. In the same manner, iPS cells could be use to grow clones. And that would require embryonic involvement.Bioethics Defense Fund President Nikolas T. Nikas commented that the news of human cloning being achieved at the blastocyst level, highlights the necessity of state and federal legislation banning the creation of cloned human embryos for any purpose.
"If true, the creation of human beings at the embryonic stage of life by cloning marks a new and decisive step toward turning human reproduction into a manufacturing process. The creation of human embryos for the purpose of exploitation as raw material for lab experiments is grossly immoral and a blatant violation of human dignity," said Nikas (Bordlee, 2007).
Do we need mothers?
In this twilight world of the future, who would be the mothers, willing to go through nine months of gestation in her womb to produce children for the sake of organ and tissue donation? Alternatives are being explored by scientists.
Well, maybe we don't need wombs.
Researchers are working to create a totally artificial womb. A team of scientists from Cornell University's Weill Medical College announced that they had succeeded, for the first time, in creating an artificial womb lining. The scientific team, led by Dr. Hung Chiung Liu of the Centre for Reproductive Medicine and Infertility, stimulated cells to grow into uterine lining, using a cocktail of drugs and hormones. According to an article in the Guardian by Jeremy Rifkin headed "The end of pregnancy--Within a generation there will be probably be mass use of artificial wombs to grow babies," the goal of the research is to help infertile couples by creating an entire womb which could be transplanted into a woman (Rifkin, 2002).
During an interview at the American Society for Reproductive Medicine Conference in 2001, Dr. Liu was asked: "Is it ... science fiction to say maybe in the far future you could have a real breathing embryo and have a child in the laboratory?"
"That's my final goal," Dr. Liu replied. "I call it an artificial uterus. I want to see whether I can develop an actual external device with this endometrium cell and then probably with a computer system simulate the feed in medium, feed out medium... and also have a chip controlling the hormone level." While conceding that such baby-incubating technology lies in the future, Dr. Liu said, "I believe this can be achieved, we could possibly have an artificial uterus so then you could grow a baby to term (Rosen, 2003)."
Illustration for the cover of Focus Magazine Italy on the design and development of a artificial womb |
Indeed, maybe we don't even need mothers.
Yosinori Kuwabara and his colleagues, working in a small research laboratory at Juntendou University in Tokyo, are developing the first operational artificial "motherless" womb--a clear plastic tank the size of a bread basket, filled with amniotic fluid at body temperature. For the past several years, Kuwabara and his team have kept goat foetuses alive and growing for up to 10 days by connecting their umbilical cords to two machines that serve as a placenta, pumping in blood, oxygen and nutrients and disposing of waste products. While the plastic womb is still only a prototype, Kuwabara predicts that a fully functioning artificial womb capable of gestating a human fetus may be a reality in less than six years (Rifkin, 2002).
Research is proceeding to even create artificial eggs and sperm. Scientists at Stanford University claim they've found a way to make human embryonic stem cells turn into the types of cells that ultimately form sperm and eggs, according to a study reported in the journal Nature.
CBS News medical correspondent Dr. Jennifer Ashton explained how the scientists did it: "They took unused embryonic stem cells ... and then they put them in a lab, gave them some special cocktail of nutrients, proteins, some chemicals, and coaxed them into developing into early sperm and early eggs (Artificial Sperm and Eggs?, 2009)."
But, whether one uses an actual embryo or a mother, or an iPS stem cell, or an artificial embryo, mother, womb, egg, sperm or whatever, if the end result is a human life, you have to deal with the ethical questions regarding that human life.
And what about ownership?
What about ownership involving these discoveries? The person who discovered the method to create the first line of human embryonic stem cells is Dr. James Thomson, University of Wisconsin, listed as the "inventor of human embryonic stem cells."
In 1998, the U.S. Patent and Trademark Office (PTO) issued a broad patent claiming primate (including human) embryonic stem cells, entitled "Primate Embryonic Stem Cells" (Patent 5,843,780). On 13 March 2001, a second patent (6,200,806) was issued with the same title but focused on human embryonic stem cells (Biological patent, 2009).
The owner of the embryonic stem cell patents is the Madison-based Wisconsin Alumni Research Foundation (WARF), a technology-licensing organization associated with the University of Wisconsin, with $1.6 billion in assets.
The 1998 patent reads as follows:
We claim: 1. A purified preparation of primate embryonic stem cells which (i) is capable of proliferation in an in vitro culture for over one year, (ii) maintains a karyotype in which all the chromosomes characteristic of the primate species are present and not noticeably altered through prolonged culture, (iii) maintains the potential to differentiate into derivatives of endoderm, mesoderm and ectoderm tissues throughout the culture, and (iv) will not differentiate when cultured on a fibroblast feeder layer (Loring, 2007).
A patent on life: U.S. patent for "Embryonic stem cells and methods of obtaining them" |
By claiming ownership of a stem cell's ability to replicate itself in vitro, that is in a Petri dish in the laboratory, WARF is claiming ownership of the very process that governs the creation of life.
These patents are being challenged by group of three individuals: Jeanne Loring, director of the Center for Regenerative Medicine at The Scripps Research Institute, Dan Ravicher, an attorney who has founded the Public Patent Foundation in New York to challenge patents that threatened the public interest, and John Simpson of the Foundation for Taxpayer and Consumer Rights in Santa Monica, California. On 17 July, 2006 they requested that three "Primate Embryonic Stem Cell" patents be re-examined by the US Patent and Trademark Office (Loring, 2007).
Loring said the patents should never have been granted because earlier work by other researchers made the science "obvious and therefore unpatentable."
However Simpson's non-technical reason was more to the point. "It's absolutely absurd that one person or organization could own the rights to life itself," he said. (Stem Cell Patents Come Under Fire, 2006).
Why is it absurd? Because looking at human life as capable of being owned, even at the stem cell level, is opening the doors to slavery. And slavery presumes the right to that person's life. Further, it is scientific arrogance to claim that the discovery of a life process created by God is a human invention.
However, to date, these patents have been upheld by the patent office, meanng that the University of Wisconsin Alumni Research Foundation will continue to control primary intellectual property rights to embryonic stem cell research in the United States (Foley, 2008)
As morality collapses within the scientific community, so this community begins to collapse itself.
Stem cell fraud
Scientists have struggled for years to produce a stem cell line of cloned human beings. Several years prior to Dr. Wood's successful cloning of himself, a South Korean biomedical scientist Woo-Suk Hwang claimed to have succeeded in creating human embryonic stem cells by cloning. Time Magazine featured him in its choice of "People Who Mattered 2004," in its Person of the Year issue, writing that:
A veterinarian by training, Hwang began to research cloning for a practical purpose: he wanted to create a better cow. But his work didn't stop in the barnyard. Hwang and his team at Seoul National University became the first to clone human embryos capable of yielding viable stem cells that might one day cure countless diseases. While such research raises troubling ethical questions, Hwang has already proved that human cloning is no longer science fiction, but a fact of life (People who mattered, 2004).
Disgraced stem cell scientist Hwang Woo-suk guilty of fraud |
A panel of Seoul National University experts later found that Hwang had faked the results of the stem cells lines he claimed to have created. He was indicted on embezzlement and bioethics law violations involving millions of dollars in privately donated research funds he had accepted for the fete. On Oct. 27, 2009 Rueters carried the headline: "South Korea stem cell scientist guilty of fraud." After a trial that stretched over three years, the court sentenced Hwang--once a scientist with rock-star like status for bringing South Korea to the forefront of stem cell studies--to two years in jail, suspended for three years (Kim and Herskovits, 2009).
Why is there fraud in the stem cell field? Possibly because where absolute standards are violated, such as the absolute right of all people created on earth to live, then the ends justify the means and truth does not count. The reasoning could conceivable be that if one can advance stem cell research which will supposedly benefit mankind, why not lie, if that is what it takes? And where truth does not count, you do not have science.
The truth is that stem cell research at the embryonic level takes lives. President Bush, in signing his first veto rejecting legislation that would ease limits on federal funding for embryonic stem-cell research, stated why such research is unethical. As he signed the bill, he was surrounded by 18 families who had "adopted" frozen embryos that were not used by other couples, and then used those leftover embryos to have children.
Families who had adopted "leftover" embryos surround President Bush as he signs veto |
"Each of these children was still adopted while still an embryo and has been blessed with a chance to grow, to grow up in a loving family," he said. "These boys and girls are not spare parts (Roberts, 2006)."
A look into the future
Practically speaking, where could this lead us, waiving ethical constraints?
Here is a example, futuristic, yes, but not illogical. What one can imagine as possible, can happen.
Let us say that we have a President some time in the future, President John Doe. For national security reasons, it would obviously be in the national interest to have him in good health and optimally functioning.
Congress, let us say, passes the Presidential Cloning Act of 2020, authorizing the creation of a Presidential cloning bank. Skin cells are taken from President Doe and by means of nuclear transfer or cell regression, placed in ten eggs. These eggs are then implanted in five women, who have agreed, for a government stipend, to carry these stem cells of the President to term. As a backup, five artificial wombs have been seeded with the five other clones.
Following birth nine months later, these clones (they all survived) are raised with the best of treatment to make sure they are healthy specimens, suitable some day for organ service, if the President so needed one. In the mean time, these Presidential clones live a good life, with the exception that they have few friends, primarily only medical staff at a place in which they reside called Clone Camp David
Let us say one day a medical exam of the President discloses that he needs a new heart. It is decided to sacrifice the most healthy, Clone 8. However, on learning of his fate, Presidential Clone No. 8 filed an injunction, saying that he is a person, and that surgically removing his heart would be murder.
The case is brought all the way to the U.S. Supreme Court, where it is adjudicated. The justices decided that it cannot be a murder, for Clone 8 is not a person by reason of Roe v. Wade. In the majority opinion, it was determined that since Roe. v. Wade held that "the unborn have never been recognized in the law as persons in the whole sense," mere passage of that non-person from the womb would not grant personhood. Further, the decision found that since Clone 8 was a mere copy of the President, copies are not persons, but merely clones, which do not count as human beings.
The majority opinion also found that since the patent was held by the University of Wisconsin for the cell line from which Clone No. 8 was made, ownership of the being so created was also held by that institution.
Following signed permission by the university, Clone 8 was taken from Clone Camp David, strapped to an operating table at a secret location, anesthetized, his heart surgically removed, and transplanted into President John Doe, who recovered and thrived with his new heart. Clone 8 was buried in Arlington Cemetery as a national hero.
The point? The point is this. When you transgress moral laws, such as "thou shalt not kill," you enter a world were eventually everything goes.
Aldous Huxley in his novel Brave New World foreshadowed this world, writing, "One by one the eggs were transferred from their test-tubes to the larger containers; deftly the peritoneal lining was slit, the morula dropped into place, the saline solution poured . . . and already the bottle had passed on through an opening in the wall, slowly on into the Social Predestination Room.''
And so did British author Mary Shelley, in her novel Frankenstein or The Modern Prometheus. The book recounts a story about a scientist, Victor Frankenstein, who learns how to create life, assembling a monster in his laboratory out of body parts from the "dissecting room and the slaughter-house." The creature came to be known as "Frankenstein." She wrote how one night the scientist stood over his work:
It was on a dreary night of November that I beheld the accomplishment of my toils. With an anxiety that almost amounted to agony, I collected the instruments of life around me, that I might infuse a spark of being into the lifeless thing that lay at my feet. It was already one in the morning; the rain pattered dismally against the panes, and my candle was nearly burnt out, when, by the glimmer of the half-extinguished light, I saw the dull yellow eye of the creature open; it breathed hard, and a convulsive motion agitated its limbs.
In this Brave New World we are approaching today, Dr. Frankenstein would rule. And it is not the potential clones who would be Frankensteins, but their creators. Without proper ethical and legislative restraints, we, as members of this nation, run the risk of participating in a moral monstrosity. We run the risk of creating two classes: those who deserve to be cured and those who deserve to be sacrificed.
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