The Catastrophic Cloning Caper

On the 10^th of January, 2006, the Seoul National University (SNU) Investigative Committee released the conclusions of its December 15, 2005-January 9, 2006 investigation.  They determined that Professor Woo Suk Hwang and his co-workers had fabricated all the significant results of their landmark 2004 and 2005 papers that appeared in the journal Science.  The 2004 paper reported the first definitively successful attempts to establish human embryonic stem cell lines that could differentiate into a wide variety of cell types by means of somatic nuclear cell transfer (SCNT).  The 2005 paper demonstrated that nuclei from the cells of patients could be used to make patient-specific human embryonic stem cells via SCNT.  Such cells were hailed as a means to “treat disease and injury at the cellular level at the clinic.”  However, upon further investigation, these results were shown to be completely bogus.  On January 16^th, 2006, the President of SNU, Un-chan Chung issued a statement that publicly apologized to all Koreans for Hwang’s “grievous misconduct,” and stated that there “can be no science deserving of that name without honesty and integrity.”

Of perhaps even greater concern is the manner in which Hwang procured the tremendous quantity of unfertilized human eggs.  On February 2, 2006, Korea’s National Bioethics Committee confirmed the ugly rumors that Hwang, as the principal investigator of a government-funded research laboratory, had coerced junior, female members of his research team to donate their eggs.  Even though Hwang had acknowledged the use of approximately four hundred unfertilized eggs, it turns out that he used more than 2,221 eggs and some thirty-five women’s groups plan to sue the South Korean government for funding a rogue researcher who brazenly disregarded the bioethical guidelines for egg procurement.  Worse still, 20% of the women who donated eggs from Hwang’s work were not informed of the risks and some are even suffering side effects from the procedure.

Hwang’s dishonesty has tremendous implications for the stem cell debate.  What hangs in the debate is not just some arcane technology done by scientists at work benches in secluded laboratories, but our future definition of a human being and the limits to which we will go to find clinically viable cures to modern maladies.  If we leave this debate to those who wish to ignore such questions and get on with their embryonic manipulations, then we forfeit the right to be heard on the subject of the unborn.  If we fail to make a cogent or persuasive case because we are poorly informed, then we will be dismissed from the discussion before it has even begun.

Dissection of a Deception

On February 12, 2004, Hwang and his colleagues announced that they had successfully cloned thirty human embryos and harvested stem cells from them.  Embryo cloning utilized unfertilized eggs (oocytes) from female volunteers that still contained the cloud of follicle cells that typically surround human oocytes (the female gamete or reproductive cell).  They allegedly removed the nuclei from the collected oocytes, a process known as enucleation, transferred nuclei from the surrounding follicle cells into the nucleus-less oocytes and then administered low-level electric shocks to the occytes to activate them.  The nucleus is the structure inside cells that contains the chromosomes, which are composed of DNA.  Our genes, which determine if we are tall or short, light or dark, blue or brown-eyed, are encoded by DNA.  Oocytes only possess half the number of chromosomes that the rest of our cells possess and transferring a whole cell’s worth of human chromosomes into an enucleated oocyte can, theoretically, induce the oocyte to behave like a fertilized egg.  Fertilized eggs or zygotes continuously divide to form, in about five days, a sphere of cells called a blastocyst.  Blastocysts contain an outer layer of cells called trophoblast cells and an internal clump of cells called the inner cell mass (ICM).  Of the 242 eggs reportedly collected, thirty oocytes behaved like fertilized embryos and grew to the blastocyst stage.  Of these thirty blastocyst-stage embryos, twenty of them were of high enough quality to provide isolated ICM cells for embryonic stem cell cultures.  Of these twenty ICM cell cultures, only one grew as a proper cell line.  This paper represented was the first time SCNT was successfully used to make human embryos and one embryonic stem cell line, SCNT-hES-1 was said to have been made from the one of the embryos generated in this fashion.  Essential to the success of these experiments was the collection of unfertilized human oocytes from sixteen female volunteers, who, we were told, provided their eggs without financial compensation or coercion.  These results were published in the March 12, 2004 issue of Science and the editorial in this same issue by Editor-in-Chief Donald Kennedy stated that “our domestic moral terrain is not readily exportable:  U.S. politicians can’t make ground rules for everyone, and they don’t have a special claim to the ethical high ground.”

Questions surfaced soon thereafter in May, 2004, when the British scientific journal Nature discovered that at least some of the eggs used by Hwang’s group came from junior members of his own research team.  This is problematic because obtaining human eggs is painful and risky.  Volunteers are required to take fertility drugs that cause the ovulation of many eggs at once.  These drugs have their own set of side effects and can cause significant health problems in even young, healthy females.  Since Hwang is the principal investigator of his own research group, collection of eggs from his own lab workers could appear to be a case of an overbearing boss pressuring his female graduate students to give up their eggs, which is hardly an ethically proper thing to do.  Regardless, Hwang denied any wrong doing but dutifully suspended his research until a new set of national bioethics laws were established the following year.  On January 1, 2005, the new bioethics law came into effect and twelve days later Hwang’s embryonic stem cell research was the first work approved by the South Korean government under the new bioethics law.

In May, 2005, Hwang’s group announced yet another landmark advance.  This time Hwang and others claimed to have established eleven patient-specific embryonic stem-cell lines that were derived by means of SCNT.  They used nuclei from cultured fibroblasts (a cell from skin biopsies that grows rather well in culture) taken from patients who suffered from a variety of conditions that ranged from genetic immunodeficiency diseases to spinal cord injuries for SCNT.  The fibroblast nuclei were transferred into enucleated oocytes from female volunteers, and grown to the blastocyst stage.  The blastocysts were disassembled to retrieve the ICM cells, which were cultured to establish patient-specific embryonic stem cell lines.  Hwang further claimed that because he had used no animal feeder cell lines to culture these cells, they were potentially free of animal products and could be used for cell transplantation therapy in a clinical setting.  This paper was glorified throughout the international scientific community as a major break breakthrough in the medical use of person-specific cell lines.  “”This is spectacular work,” opined Harvard Medical School stem-cell research George Daley.  “It just moves the field forward so quickly.  It really convinces you that this is practical and feasible.”

Despite the fact that Hwang was at the zenith of his fame and a national hero at this time, his clout began to quickly unravel.  First of all, questions and troubling accusations about how he procured his eggs not only remained, but intensified.  On November 12, 2005, Hwang’s American co-author Gerald Schatten of the University of Pittsburgh cut all ties with Hwang and Seoul National University.  Schatten cited significant bioethical violations concerning oocyte procurement for the 2005 Science paper as the reasons for his disengagement from Hwang, but he refused to specify the exact nature of Hwang’s malfeasance.  Approximately two weeks later, a Korean co-author of the 2005 Science paper, Sun Il Roh of MizMedi Hospital in Seoul, admitted that at least twenty of the eggs he gave to Hwang for his 2004 Science paper, were acquired through payments to donors, but he insisted that Hwang did not know that the egg donors had been paid for their oocytes.  The next day, the Seoul-based Munhwa Broadcasting Corporation (MBC) aired an investigative news report that featured further evidence that Hwang had used eggs from junior members of his lab.  Two days later, Hwang admitted that he had used eggs from junior members of his lab and paid donors and that he had done so with full knowledge of this impropriety.  He resigned his official positions but vowed to continue his research.  Thus Hwang had violated established bioethical guidelines for oocyte procurement and lied about doing so.

On the first of December, 2005, MBC reported the results of an initial test that called into question the work from his 2005 Science paper.  MBC acquired five samples from the patient-specific cell lines allegedly made by Hwang in his 2005 Science paper and sent them to an independent lab for corroboration, along with tissue samples from the patients whose nuclei were used to supposedly construct the patient-specific embryonic cell lines.  DNA analyses from this independent lab showed that the DNA from one of the patient-specific cell lines did not match the tissue sample as it should, which raised the distinct possibility that the embryonic stem cell lines were not made from cloned embryos.  This prompted SNU to mount its own investigation into Hwang’s research.  Four days later, Hwang’s collaborator Sun Il Roh struck again and told MBC that Hwang had privately admitted to him that there were no cloned embryonic stem cells.  The next day, Schatten and Hwang wrote to the journal Science to retract their May, 2005 paper.  Apparently mounting problems confirming their own results drove them to admit defeat before the investigation had even ended.  On December 23, SNU announced in a televised press conference the results of their initial investigation into Hwang’s work and concluded that the data represented in the 2005 Science paper came from only two cell lines and not eleven as claimed in the paper.  Furthermore, Jung Hye Roe, chief of Seoul National University’s research office, said in this press release that the errors in Hwang’s paper, “cannot be some error from a simple mistake, but can only be seen as a deliberate fabrication.”  He continued and stated that “Professor Hwang’s Science paper violates the most fundamental ethics of scientific research.”  Hwang continued to deny any all accusations of fraud, but did tender his resignation to the university.  He insisted, however that the two remaining, untested frozen stem-cell lines would be verified, saying “I’d like to repeat:  patient-tailored embryonic stem cells are South Korean technology.”  However on December 29, the SNU investigative team showed that the two remaining cell lines were not patient-specific embryonic stem cell lines, but were lines created from normal embryos made by in vitro fertilization.

Hwang’s troubles, however, did not stop there.  On January 4, 2006, the South Korean investigative news program PD Notebook was poised to air a news piece that accused Hwang of coercing a junior member of his research group into donating eggs for research.  Apparently she felt obligated to do so because she had accidentally destroyed some oocytes early in the experiment.  Further troubles also brewed as the The Korea Times reported that government prosecutors were strongly considering charging Hwang with fraud after the completion of the SNU investigation.  The case against Hwang seemed rather ominous, since Hwang’s group received more than three billion dollars (equivalent to three million dollars, US money) for research from the South Korean ministry of science and technology last year, and some twenty-four billion dollars were awarded to build and establish new facilities.

On October 26, 2009, Hwang was sentenced to two years in prison at the Seoul Central District Court.  He was found guilty of embezzlement and bioethical violations but was cleared of fraud.

The Korea Times reported that the light sentence was motivated by judge Ki-ryul Bae’s sympathy for Hwang’s apparent dedication to Korean biotechnology and his stated remorse.

Why Did He Do It?

Why did Hwang fabricate his data?  Why did he take the path of temporary fame and notoriety only to have his life, career and reputation completely destroyed?  Many have speculated that the South Korean mindset that drives people to work seven days a week, fourteen hours a day and is satisfied with nothing less than earth-shaking success drove him to do this.  I find this explanation rather unsatisfying because if the South Korean work ethic is to blame, then South Korea should be a breeding group for fraud and unethical behavior and this is clearly not the case.  Instead, it seems to me that the problem lies with the subject of Hwang’s work – human embryonic stem cell research.

Human embryonic stem cells are derived from ICM cells of blastocyst-stage human embryos.  In order to make embryonic stem cell lines, the researcher is required to destroy the outer layer of cells, the trophoblast, by various means in order to harvest the ICM cells.  The description of the destruction of a human embryo in Hwang’s is so matter-of-fact that it evinces little more than a yawn from the reader.  In Hwang’s 2004 Science paper, we read the following words, “A total of 30 SCNT-derived blastocysts were cultured, 20 ICMs ere isolated by immuosurgical removal of the trophoblast, and one ES cell line (SCNT-hES-1) was derived.”  In other words, the blastocyst-stage embryos were incubated with antibodies that bound to the trophoblast cells in the presence of serum.  Serum contains complement proteins, which bind to antibodies that are bound to cell surfaces and damage the surfaces of those cells.  The incubation of these blastocysts with these antibodies in serum destroys the surfaces of the trophoblast cells, killing them and liberating the ICM cells.

No matter what technique is used or how it is done, the simple, undeniable biological fact remains that harvesting ICM cells from a blastocyst-stage human embryo destroys the embryo and ends whatever potential that embryo might have had to generate a human baby.  However, within human embryonic stem cell research, blastocysts are not regarded as having even an incipient sense of human personhood.  On page 153 of, The Proteus Effect:  Stem Cells and Their Promise for Medicine, Ann B. Parsons quotes stem cell researcher Normal Frost’s as “long list of reasons” why a young embryo is not a human person:

“An embryo doesn’t look like a person…Nor does it experience suffering, which is part of why we care about what a person is.  And even the most ardent advocates of an embryo-as-person don’t ask that embryos be counted in the census; they don’t ask that they be included in the tax code deductions; they don’t ask that they be covered by health insurance, and they don’t ask that they have funerals.”

In Frost’s view, our personhood is reducible to how we look, function and are regarded by others.

With regards to functioning, as in Frost’s case with suffering, someone must be a person in order to suffer, but one can be a person without suffering. Frost seems to commit himself to the flawed philosophical position of functionalism, which confuses being with doing or essence with function or behavior. Suffering, speaking, thinking and arguing are all characteristics of persons, but does one cease to be a person when one is not suffering, thinking, speaking or arguing? The answer is certainly no. When we go to sleep, if we are placed under anesthesia or faint we stop using our gifts of consciousness, yet we do not stop being human. When topical anesthetics are used to numb the pain of localized surgical procedures, we do not feel pain, but are still fully human. Essence, what someone or something actually is, must precede function, because function depends on essence and not the other way round. Thus Frost’s first criterion is seriously flawed.

As for looks, people drastically change throughout their lives. Which appearance is the standard one against which all must be measured: someone who is one year old, three years old, twenty-five years old or seventy-five years old? Furthermore, circumstances can easily affect one’s appearance. The campus minister at my institution, who usually sports a robust beard, is undergoing chemotherapy for cancer and has lost all of his cranial and facial hair and looks so different that even those who know him well fail to recognize him, but he is still fully human. The same can be said for those who have suffered debilitating accidents that have affected their appearance. If we do not use the changes in appearance that occur throughout someone’s life to affect our evaluation of them as a person, then why would we use such an evaluation for someone who has yet to experience birth? Clearly using how someone appears at a particular stage in their life as a means to define them as a human person or a non-human person is equally absurd as using function.

Finally, the manner in which someone or a government may or may not acknowledge you is an equally fallacious means of determining one’s humanity. Does giving someone a funeral make them a person? If this is the case then the countless victims of genocides whose bodies were rolled into mass graves and never had the benefit of a funeral are not persons, which is both absurd and cruel. Does being a tax deduction for someone else or being counted in a census establish one’s personhood? Clearly the answer is a resounding no. One can be a person and not have a funeral, fail to be regarded as a tax write-off or be missed in a census. One has to already be a person in order to be given a funeral, regarded as a tax-write-off or recognized by a national census, but having a funeral, being regarded as a tax write-off or being acknowledged by a national census does not make one a person. Once again the arguments confuse essence and function. Thus none of Frost’s criteria appear to provide any basis for dismissing the embryo as an entity worthy of protection.

Frost and others who hold his point of view could easily counter that blastocyst-stage embryos do not have a brain, and this prevents us from attributing human status to them. The problem with this assertion is that it is really only half right since one could just as easily point out that a blastocyst-stage embryo does not have a brain yet. Nothing else but a human being has the capacity to grow a human brain. This simple fact makes all designations of blastocyst-stage embryos as human life but not human persons somewhat problematic.

A Necessary Risk?

In a letter to the members of the United Nations General Assembly concerning the ban on human cloning, the International Society for Stem Cell Research (ISSCR) wrote that “Practiced appropriately, nuclear transfer research is about saving and improving lives. It is fundamentally different from human reproductive cloning; appropriate uses of nuclear transfer research produce stem cells, not babies.” ISSCR concluded this letter by stating that “[S]uch a declaration would inhibit the search for new treatments for mankind’s most devastating diseases.” Apparently the ISSCR believes that research on embryonic stem cells is the only way to advance cell replacement therapy, and a ban on therapeutic human cloning would stifle such advances.

In contrast to the statements made by the ISSCR, cell replacement therapies are presently being done in humans, but not with embryonic stem cells. Instead somatic stem cells (also known as adult stem cells), which are embedded in various tissues and divide to maintain and repair these tissues, have been co-opted for treatments of a variety of conditions. Using somatic stem cells, scientists and clinicians have treated patients for:

a) genetic diseases like juvenile autosomal recessive osteopetrosis, which is usually fatal before the age of five; b) autoimmune diseases like Crohn’s disease, which sentence patients to a life of painful gastrointestinal inflammatory outbreaks, c) anemias like sickle-cell anemia and other types of anemia; d) inherited immunodeficiency diseases that condemn children to lives within sterile bubbles, and e) neurological diseases like Parkinson’s disease. Physicians have also used a) somatic (adult) stem cells from fat to repair a girl’s broken skull; b) circulating blood- or marrow-derived progenitor cells to mend ailing hearts; c) a patient’s bone marrow with recombinant Bone Morphogen Protein-7 (BMP-7) to reconstruct the jawbone of a former cancer patient, d) oral mucosal epithelium to fix damaged corneas and e) neuronal cell transplants to improve the cognitive function of stroke patients. These are but a small sampling of a large cadre of successful treatments achieved with somatic stem cells, and up to sixty-five different medical conditions have been treated with somatic stem cells. In light of the successes of these cells, one could readily ask, “What is the point of embryonic stem cell research if we already have a less controversial treatment regime that already works well?”

The National Institutes of Health Stem Cell site’s Frequently Asked Questions answer this question with this assertion:

“Human embryonic stem cells are thought to have much greater developmental potential than adult stem cells. This means that embryonic stem cells may be pluripotent—that is, able to give rise to cells found in all tissues of the embryo except for germ cells rather than being merely multipotent—restricted to specific subpopulations of cell types, as adult stem cells are thought to be.”

There are two problems with this assertion. Somatic stem cells show many signs of not being nearly as restricted in their developmental capacity as they once were thought to be. For example in the laboratory somatic stem cells from bone marrow can differentiate into cells from the blood, lung, liver, GI tract, muscle, skin, heart, pancreatic islets, nervous system, kidney, retina and spleen. Umbilical cord blood stem cells seem to have the ability to form cells from all the major body tissue types. Therefore cries of “not as versatile as embryonic stem cells” seem to lack substance.

Secondly, somatic stem cells have the uncanny ability to grow within damaged tissue and cease growth, but embryonic stem cells, even after they have been differentiated in the laboratory, can still overgrow and form tumors, or participate in “heterotropic differentiation” in which they form inappropriate tissues in the wrong place (e.g., fat tissue in the heart, bone tissue in the brain etc.). The injection of embryonic stem cells into the knee joints of mice with severe combined immunodeficiency caused the formation of tumors, which eroded the knee. Similarly, transplantation of insulin-expressing beta cells derived from embryonic stem cells into diabetic mice also caused tumors. Therefore, even though the ability of embryonic stem cells to cause tumors decreases after they are cultured and form embryoid bodies (EBs), these cells still apparently maintain a healthy ability to overgrow and form tumors.

If these were the only problems with embryonic stem cells, one might be able to shrug and say that further research will somehow solve this problem. However, larger problems obstruct the use of embryonic stem cells in the clinic. First of all, work in the laboratory of Mahendra Rao, former head of the stem cell group at the National Institute on Aging (NIA), has shown that culturing human embryonic stem cells at length causes the cells to accumulate mutations that make them completely unusable for therapeutic purposes. As stated in the abstract of his 2005 Nature Genetics paper, “… eight of nine late-passage hESC lines had one or more genomic alterations commonly observed in human cancers….” Such instability suggests that human embryonic stem cells are usable only just after they are made and must be reestablished afterwards for further therapeutic use. Such a finding does not bode well for the future of these cells in medicine.

Secondly, the use of embryonic stem cells is precluded, since the immune system of the patient will certainly reject these cells once they are transplanted. Such immunological rejection is mechanistically similar to the rejection of a transplanted organ and is known as the “graft versus host” response. To circumvent this problem, making patient-specific embryonic stem cells by means of somatic nuclear transfer was instituted by Hwang and his colleagues, but has been shown to be completely bogus. Therefore, this route is still presently not open to those who wish to use embryonic stem cells for therapeutic purposes. However, the waters are even muddier than we might first assume because rodent embryonic stem cells made by means of somatic cell nuclear transfer, and transplanted into mice with the same immunological profile as the transplanted stem cells, have still shown rejection by the host. Therefore, even if we can succeed in making patient-specific embryonic stem cell lines, it is not at all certain that these lines will prove useful in treating patients who need cell replacement therapy.

Even more problematic is the enormous quantities of high-quality human oocytes for the generation of patient-specific embryonic stem cell lines. Mind you, essentially everyone in the embryonic stem cell debate agrees that ethical procurement of human eggs is an important issue, and virtually all embryonic stem cell research programs possess bioethical guidelines for egg procurement. However, somatic nuclear transfer is an inherently inefficient procedure. Peter Mombaerts reports in the September 30^th, 2003, edition of the Proceedings of the National Academy of Sciences that the average efficiency rate, when using mouse cells, for removing the nucleus of an oocyte and successfully transplanting it with a new one so that it divides and grows into a blastocyst-stage embryo is 0.15 %, and the efficiency of procuring embryonic stem cell lines from such blastocysts is 8.2%. Such numbers do not instill a great deal of confidence in the establishment of patient-specific embryonic stem cell lines for ailing patients. In fact, Mombaerts conservatively estimates that to establish two to three patient-specific embryonic stem cell lines per patient, scientists would require about 100 oocytes for each patient. Since the cost of procuring each oocyte is approximately $1000-2000 each, it would cost something on the order of ~$100,000-200,000 per patient to establish the lines required to cure the patients. If we were to ask the medical establishment to eliminate only one disease, such a project would cost a prohibitive amount of money and require a ridiculous quantity of oocytes. Finding enough young, healthy female volunteers who are willing to undergo the harshness of fertility treatments to produce enough eggs for research or therapeutic purposes is problematic to say the least and creates opportunities for unscrupulous individuals to exploit women in the marketing of human tissue.

These concerns should give us pause when advocates of embryonic stem cells state that we are obligated to promote and investigate this line of research as a mode of treatment, since its inherent limitations, ethical problems, and lack of demonstrated efficacy all militate against pursuing it further.

Conclusion

Duke Divinity School’s Amy Laura Hall argues that in vitro fertilization objectifies the creation of human life and demotes it to a means to satisfy a desire to give birth instead of recognizing the sacred gift that the creation of each human life represents. In the same way, embryo cloning and embryonic stem cell formation objectifies slightly later stages of human development and views the embryo as a means to an end. We are on the slippery slope where later and later stages of human life are objectified all because we see a potential use for them. In the July 2005 edition of the journal Brain, Mendez and others discuss the post-mortem examinations of the brains of Parkinson’s patients who had undergone transplantations with fetal midbrain tissue. It seems that if embryos are efficacious for treatment, then fetuses should serve us in this fashion as well. Where does it stop? Will parents who need treatment eventually be able to assert their rights to the cells of their sons and daughters?

Furthermore, how we treat the weakest members of the human race among us, seen or unseen, deeply influences how we treat those within our reach. How would you wish to be treated if you were one of the weaker members of society? Now we see why this is not an esoteric issue that should only be debated by professors, scientists and politicians. It is a debate for the soul of our society.