Controversial Scientific Research And
Policy Co-ordination: Issues Raised
By The Research Of Woo-Suk Hwang
Candidate Number: 27184
Supervisor: Professor Julian Savulescu
Word Count: 2989
Contents:
Page
1
Contents
2
Abbreviations
3
Main Text
3 Hwang – Outlining The Issues
4 Pressures Facilitating Misbehaviour
4
Funding And Publications
5
Media And The General Public
6 Lax Implementation Of Ethical Policy
6
Investors
6
Ethical Review Boards
8 General Problems In Science Raised By Woo-Suk Hwang’s Research
8
Verification
8
Journals
9
Education
9
International Co-ordination
10 Possible Solutions
12 Concluding Comments
13
Appendix A - Background To The Hwang Case
17
Appendix B - Compromising Scientific Integrity
18
Appendix C - Fame And Pressure
19
Appendix D - Information Provided By Hwang To Donors
26
Appendix E - Oocyte Donation
28
Appendix F - Journals
29
Appendix G - Publishing, Credit Where Credit Is Due
30
Bibliography
1
Abbreviations
IRB
-
Institutional Review Board
KBA -
Korean Bioethics Association
LREC -
Local Research Ethics Committee
MBC -
Munhwa Broadcasting Corporation
NBC -
National Bioethics Committee
NIH
-
National Institutes of Health
SC
-
Stem Cell
SCRC -
Stem Cell Research Centre
SCNT -
Somatic Cell Nuclear Transfer
SNU -
Seoul National University
2
Hwang – Outlining The Issues
[See Appendix A for a more in-depth timeline]
Woo-Suk Hwang trained as a veterinary scientist and in 2003 claimed to have
developed BSE-resistant cattle, but this was never published and remains unverified.
For two related projects: ‘The Social Impact Of BSE-Resistant Cows’ (2001) and
‘Ethical Guidelines And Commercial Use Of Bio-Organs’ (2003) Hwang paid KyYoung Park $250,000 [1]. From 2002 Park had close-connections with Government,
becoming more influential in 2003 as a presidential advisor of science and
technology.
Hwang became a scientific enigma and celebrity after offering proof of cloned human
blastocysts: ‘Evidence Of A Pluripotent Human Embryonic Stem Cell Line Derived
From A Cloned Blastocyst’ [2]. Nature questioned Hwang’s ethics after an interview
indicated that oocytes used were donated by junior researchers. Hwang denied the
allegation but suspended research until the ‘Biosafety Act’ came into effect in January
2005. After resumption, Hwang told Park and Gerald Schatten, an American
collaborator, that four of six stem cell (SC) colonies he had created were infected with
Fungi. Park oversaw implementation of preventative measures but did not officially
report the incident [3]. Schatten urged Hwang to publish anyway [4] and Hwang
submitted ‘Patient-Specific Embryonic Stem Cells Derived From Human SCNT
[Somatic Cell Nuclear Transfer] Blastocysts’ [5] to Science. Later, Schatten informed
Science about allegations of illegally traded ova [6] and subsequently broke links with
Hwang because he had been misinformed about consent issues. In December,
Munhwa Broadcasting Corporation (MBC) reported that independent DNA analysis
indicated that one SC line did not match its supposed donor. Investigations were
started at both Schatten’s and Hwang’s institutions, Pittsburgh University and Seoul
National University (SNU) respectively. SNU soon found that much of Hwang’s work
was fabricated.
Hwang rose from global obscurity to Scientific American’s ‘Research Leader of the
Year 2005’ - exposure of “Korea’s Cloning King” [36] as a fraud rocked science.
Hwang’s case highlights that sound research ethics is paramount to reliable science. It
appears Hwang was a good scientist operating in an environment that was conducive
3
to misadventure. Hwang credited his ‘success’ to plentiful funds, abundant oocytes,
and a supportive political/legal environment. But these, together with ambition, also
created an environment for scientific tragedy. Hwang met with many pressures but
few constraints; the choices he made at each juncture made his eventual discrediting
acts evermore likely. The Machiavellian desire for “community recognition and
prestige” [7] in modern science cannot be underestimated nor easily mitigated. Here
the pressures scientists are exposed to and the minimal constraints they experience
will be discussed and some possible solutions forwarded.
Pressures Facilitating Misbehaviour
Funding and publications
One could argue that funding directs, if not dictates, science: without funding science
cannot be realised. Publications provide investors with information regarding the
researcher’s capabilities and therefore there is great pressure to publish. Fundingadvantage is gained from how far up the journal hierarchy one publishes. The
Research Assessment Exercise implements selective funding for universities – but
there is suspicion that the publishing journal is “given greater weight than the papers'
content” [39]. Ground-breaking papers are more likely to secure a major journal;
attract more public and/or commercial interest and be favoured by investors. Thus,
researchers could feel pressure to exaggerate their capabilities and there is a fine-line
between exaggeration and deception [Appendix B]. Luk Van Parijs was recently fired
for fabricating papers to support grant applications [8].
The majority of funding comes from Governments, companies and private investors.
Companies have a specific interest in the funding research that could improve their
profit margins. Pressure from investors can influence research; in a survey of NIH
researchers 15.5% admitted to altering their research approach under pressure from
funding sources [8]. Barnes investigated whether scientist affiliation affected research
conclusions. 106 passive-smoking review articles published between 1980 and 1995
were analysed; 37% concluded passive-smoking was not harmful. Of these 74% were
written by tobacco-affiliated authors. Barnes found to 95% confidence that
conclusions related to the affiliation of the author [9]. Given that many private donors
4
prefer to remain anonymous, this could cause serious problems in judging a
researcher’s bias.
Hwang may have felt pressure from Government. Since much of Hwang’s early
research was unpublished it is interesting that he commanded such a sophisticated lab.
His work was better known in South Korea than worldwide; but should
unsubstantiated claims of creating BSE-resistant cattle secure ~$40 million in
Government grants? There is suspicion that Hwang ‘employed’ Park to further
political support for his own research [1]. Hwang’s association with Park may have
enabled him to attain his position. Pressure on Hwang to succeed would be immense
because the nationalistic ethos of South Korea would mean Hwang’s fame reflected
well on the Government [38]; thus, providing symbiosis in the relationship.
Media and the general public
Hwang “never shied away from the strong appeals to nationalism” that fuelled his rise
to stardom. Soon after cloning his first cow, Hwang promised to "spread the Korean
people's spirit by cloning the [holy] Mount Paektu tiger". Revered by the public,
Hwang was treated like a “rock star” [37]. The government issued ‘Dr Hwang’
postage stamps depicting a paralyzed person walking again [Appendix C] and
textbooks were rewritten - one describing Hwang as a potential Nobel Prize winner
[10]. Hwang was a symbol of everything that South Korea stood for and desired, his
picture was plastered on public transport and posters were released proclaiming he
would change the world [Appendix C]. To further Hwang’s research was to further
South Korea.
At the pinnacle of Hwang’s popularity a survey indicated that 30% of women would
donate their ova to research and 45% of men wanted their partners to donate [11]. A
website (www.ovadonation.or.kr) was set-up in November 2005 for women to pledge
their eggs to research. In seven days, 800 women had signed up and the message
board was full of encouragement for Hwang. Kim Yong-Hae, a disabled 27 year old,
wrote “Please don't give up, doctor Hwang. Your research is my only hope. You
should take all of my ova if they help" [12]. “Worshipped by so many people, Hwang
[had] no choice but to accomplish even more as soon as possible so as to live up to the
expectation of his fellow country people” [13].
5
The media is crucial in stoking public reaction and stories about Hwang’s research
and its implications for the future of humankind were commonplace. Irresponsible
reporting and unfounded speculation by scientists bred misconception and false hope
within the general public and lead to extra pressure on Hwang to deliver results.
Unfortunately, some scientists allow such misconception, probably because media
attention can bring fame and funding. Schatten’s comment regarding the future of his
collaboration with Hwang is one example: “we will be able to make a person to have
[sic] immunity against HIV... his somatic cells can be cloned to produce HIV-resistant
cells” [14]. Following comments like these scientists and the media were looking for
proof; one must either produce results or lose face..
Lax Implementation Of Ethical Policy
Investors
The Stem Cell Research Centre (SCRC) invested in Hwang’s 2004 paper. Hwang’s
co-author, Shin Yong Moon, was the SCRC president and sat on its ethics committee
which “prohibits the production of human embryos for stem cell research” [15]. Thus,
it is questionable whether Moon should have worked on the project and whether the
SCRC should have donated. Similarly, it is problematic that the Government
department that invested so heavily in Hwang was also his regulator. Because Park
did not officially report the infection of Hwang’s cell lines or her intervention it was
more difficult to uncover subsequent fabrications. Park should have reported to the
President [3] and her failure to do so probably indicated to Hwang that he was
politically immune and that the government wanted him to succeed at any cost. Park
must have known that Hwang’s 2005 paper was compromised because the four
infected SC lines were included, yet she did not expose nor question Hwang.
Ethical Review Boards
The Institutional Review Boards (IRBs) of Hanyang University and SNU both
approved Hwang's research, and his proposal was quickly passed by the National
Bioethics Committee (NBC). However, it appears numerous oversights were made.
Following Hwang’s exposure, the NBC determined that Hwang failed to sufficiently
6
protect donors: he provided insufficient information on the possible risks of donation
[Appendix D] and allowed 15 women to donate more than twice [16]. They claim that
by handing out ova-donation consent forms to junior researchers in his team Hwang
broke the Helsinki Declaration - a set of ethical principles adopted by the 18th World
Medical Assembly (Helsinki, 1964) and last updated at the 52nd World Medical
Assembly (Edinburgh, 2000) to provide guidance in medical research involving
human subjects - because he did not act responsibly with a subject “in a dependent
relationship with the physician”.
Hwang’s somatic cell donors suffered from congenital hypogamma-globulinemia;
spinal cord injury; or juvenile diabetes. Magnus and Cho, two ethicists who have
provided commentary throughout the Hwang case, find it “easy to understand the
value of SCNT experiments using somatic cells donated by individuals suffering from
genetic disorders”. But they find it “difficult to understand why spinal cord injury
patients [were] recruited” because their inclusion increased the likelihood of people
inaccurately attributing therapeutic intent to the research (therapeutic misconception)
[17]. However, because none of the donors could feasibly benefit from the research
there was no reason to enrol patients rather than healthy volunteers, especially if one
were worried about therapeutic misconception. Somatic cell donors were only
required to be unique from oocyte donors [which produced its own ethical debate –
Appendix E]. The use of vulnerable groups without reason was ethically unsound.
Acknowledging Hwang’s prominence, Magnus and Cho question how truly
independent IRB members were [17], especially given allegations that Hwang
nominated some IRB members [18]. NBC head, Yang Sam-Sung, tendered his
resignation because of undeclared conflicts-of-interest (he was Hwang’s lawyer)
while reviewing Hwang’s research. Evidence suggests that Hwang was aware of
ethical issues following his 2004 paper. In January 2005, Hwang consulted Dr Jung
and together they devised some of the most ethically defensible protocols for research
conduct. However, Hwang ignored these protocols though later Hwang, and perhaps
IRB members, knowingly falsely asserted that they were being adhered to. Jung and
Hyun had to retract their paper about the ethical integrity of Hwang’s research
[19,40].
7
Collaborating with Schatten meant Hwang’s research crossed numerous regulatory
borders. Schatten’s IRB resolved, using the Federal definition, that no human subjects
were used; and because samples could not be traced back to the donor the research
was exempt from full IRB review. However, South Korean organ sharing laws
required that donors benefit preferentially if therapies are developed via research, thus
at least one scientist should have been able to link samples to donors. Therefore, while
Schatten was involved, Hwang’s research should have had full American IRB review.
The USA National Research Council – Institute of Medicine now recommends all
embryonic SC research have full IRB oversight.
General Problems In Science Raised By Woo-Suk Hwang’s Research
Having discussed the issues that culminated in Hwang’s fraud there are some other
areas that require noting.
Verification
Traditionally, science is verified via replication and bad-science identified through an
inability to replicate. However, Robert Merton found that most modern research is
never formally replicated [20]. Replication may be illegal (few institutions could have
replicated Hwang’s work) and is, by definition, non-original. Scientists are reluctant
to waste resources producing unpublishable and, in funding terms, worthless results.
Labs designed solely for replication are inconceivable given their waste of cost and
expertise.
Journals
Magnus and Cho believe journals have an obligation to publish scientifically sound
research. Journals must be satisfied with the ethical conduct of researchers and draw
attention to any ‘grey areas’. Research that crosses ethical or legal boundaries, they
state, should not be published [21]. They are claiming that journals should act as
arbitrators, ensuring a paper is scientifically and ethically sound before publication.
However, this Manichean stance may misjudge the role of journals and is arguably
unworkable in modern science [Appendix F]. The ethical issues surrounding Hwang
are still contentious and the number of authors [Appendix G] on a single paper makes
8
it unclear where responsibility lies.The role of journals in ensuring scientific and
ethical integrity is complex and remains to be resolved.
Education
Hwang’s research highlights the difference between gaining research approval and
conducting research ethically. IRB approval does not ensure ethical practice. Hyun
considers that originally Hwang’s team had very little ethical knowledge and on
moving their focus from animals to humans they applied the same concepts in ethics
as in science [Insoo Hyun, personal communication]. A study of over 900
biotechnology researchers in South Korea found that 46% had not heard of the
Helsinki Declaration; 39% had heard of it but did not know what it was; and 42% did
not know about IRBs [22]. South Korea is not the only place where
miscomprehension about ethical issues can occur. Generally, there is little ethical
education in science. Ethics is seen as integral to modern medical training; however
the University of Oxford course in Molecular and Cellular Biochemistry does not
touch upon research ethics. To assume graduates enter research fully appreciating
their ethical responsibilities is naïve at best and dangerous at worst. As the case of
Hwang vividly illustrates, researchers with insufficient ethics education are a risk to
themselves, their colleagues, their institution and to the scientific community and
public in general.
International Co-ordination
The failure of Schatten’s IRB to recognise that the Korean organ sharing law meant
full IRB review was required demonstrates the difficulty of regulating international
collaboration. Regulating SC research is a compromise between advancing knowledge
and protecting national ethical standards, Cultural diversity manifests itself as a
patchwork of legal environments [41]. Co-ordinating science trans-nationally poses
questions other than collaborations. Germany bans the derivation of embryonic SC
lines and invokes extraterritorial jurisdiction; would a German patient travelling
abroad to donate cells for embryonic SC research be legally exposed?
9
Possible Solutions
Hwang’s case highlights the numerous threats to ethical integrity faced by scientists
today. Safeguards must be put in place to facilitate good research practices. Good
research is dependent on good ethics. Education is critical to ensure that researchers
understand their responsibilities. Ethics should be compulsory in biological degrees. It
should deal with practical aspects of research: justifying the use of and working with
vulnerable groups; informed consent and rights of participants. Those working with
human subjects should take appropriate courses and satisfactorily demonstrate
relevant knowledge. This education should be renewed every few years in light of the
constant evolution of science.
A committee without conflicts-of-interest should have been able to highlight the
ethically questionable aspects of Hwang’s research proposal. Thus, ethical assessment
independent of, and in an environment separated from, the researcher is essential.
However, this assumes that Hwang’s proposal detailed the methods he intended to
use. Without auditing research to ensure guidelines are adhered to scientists have freereign once approved. Hwang was able to ignore the protocols he drew up with Jung not even asking donors to sign IRB approved consent forms [23]. Many suggest onsite monitoring by IRBs is appropriate [26]. Magnus and Cho suggest this IRB should
be independent of that approving the research [17]. Additionally, where applicable,
suitable agencies could keep patient samples for independent analysis and ensure that
cell lines are submitted to an international depository for validating.
Donors should be carefully and ethically selected; and currently, it would be ethically
advantageous to use donors who would not benefit from prospective treatments. It
may also be beneficial to set-up a donor register to ensure proper regulation of this
aspect of research. Healthy donors should be protected by ethical guidelines, just as
patients are in clinical research. To further protect donors science should work
towards reducing the misconceptions surrounding SC research. To this end, journals
could ensure that only realistic claims, with an estimated time-scale for fruition, are
published.
10
The question of whether to publish unethical research has arisen before with reference
to Nazi experiments. Many suggest that there should be limits on what is published.
Much Nazi ‘research’ had no scientific value and was a simple disregard for human
dignity; however, some was important. Dr Epstein used results of his research to help
children recover from Noma (orofacial gangrene) [24] - the scientific worth of
unethical experiments should not be lost. To prevent distribution of scientific credit
unethical research could be published anonymously.
Hwang’s case demonstrates the difficulty in assessing a paper’s ethics. Journals could
review IRB and consent forms to inform their decisions and research auditing would
support this. However, only with open debate following publication did details of
Hwang’s research and its ethical questions become apparent. Journals should publish
research such as Hwang’s because it would be ethically questionable to withhold valid
data. By highlighting questionable legal/ethical areas journals could facilitate debate
by lawyers and ethicists. Journals should determine the contribution of each author so
that, if required, responsibility for ethical lapses can be assigned.
It seems unlikely that global consensus on SC research will soon be reached. To
facilitate discussion, the ‘Hinxton Group’ [41] calls for legal clarification with regard
to SC research[ers]. There was consensus that scientists should be free to conduct
ethically defensible research in a country where such research is legal. The group is
developing a website where scientific and ethical protocols can be deposited so that
collaborating scientists can conform to a common set of protocols appropriate to both
jurisdictions and available to public scrutiny [25]. The Group’s move toward
documenting ethical and scientific policy in its global context is an important step
towards establishing global standards of ethical review.
It would be desirable to remove some of the pressures from scientists. One possible
solution is to distance researcher from funder, perhaps by centralising funds. Funds
could be directed to projects through a registered agency. Initially, funders could be
put-off by this approach. However, since many commercial investors invest to further
or protect their products, research that cannot be dismissed as investor-influenced is
more legally sound and hence beneficial. While this sounds idealistic, centralisation
11
of funds occurs within the EU. However, some contentious issues do arise: Germany
bans SC research yet its contribution may be used to fund SC research.
Concluding Comments
Evidence suggests that Hwang was originally a pioneering scientist, and nuclear
extrusion techniques he developed have furthered cloning research. However, the
extreme pressures of his work environment complemented by lax implementation of
ethical policy and his ambition led Hwang to make grossly unethical decisions that
compromised his integrity. Hwang personifies the fact that good science requires
good ethics.
With Thanks to:
Alison Murdoch, Debra Matthews, Jung Kyu-Wong, Minou Friele, and Insoo Hyun
12
Appendix A – Background To The Hwang Case:
Pre-2004:
In 2003, Hwang claimed to have developed BSE-resistant cattle but this, and much of
his early work, was unpublished.
Related to this work, Hwang donated $250,000 between 2001 and 2004 to Ky-Young
Park, a biologist at Sunchon National University.
Park undertook two projects for Hwang: ‘The Social Impact of BSE-resistant cows’
(2001) and ‘Ethical Guidelines and Commercial Use of Bio-Organs’ (2003).
Park had close-connections with Government policy-makers from 2002 and often
acted as an unofficial mediator between Hwang and Roh Moo Hyun’s Government;
becoming more influential in 2003 as a presidential advisor of science and
technology.
2004:
Hwang published ‘Evidence of a Pluripotent Human Embryonic Stem Cell Line
Derived from a Cloned Blastocyst’ [2]. This was the first time anyone had offered
proof of a cloned human embryo, let alone successfully extracted SCs from it.
Ky-Young Park was listed as a co-author.
Nature questioned the ethical framework under which Hwang’s research was
conducted after an interview indicated that eggs donated by junior researchers were
used.
Hwang denied such allegations but voluntarily suspended this research until new
Bioethics Laws (Biosafety Act of 2003) came into effect.
The KBA asked Hwang to answer questions about recruitment of egg donors and
funding sources. They recommended that the National Human Right Commission
investigate the case, but the commission’s bioethics committee did not review specific
research projects [15].
Hwang and Shin Yong Moon declared that they did not consider the KBA neutral
because it advocated “restricting the pace of biomedical advancements” [26].
Between suspension of his research and the new Korean Biosafety Act becoming law,
Hwang collaborated with Gerald Schatten, a primate researcher at the University of
Pittsburgh.
13
Using techniques for extrusion of oocyte DNA developed by Hwang, Schatten cloned
the first monkey embryos from which SCs could be removed [27]. Though a live birth
was not achieved Schatten’s group successfully developed embryos to the blastocyst
stage.
Success was seen to be validation of Hwang’s techniques for somatic cell nuclear
transfer (SCNT).
January 2005:
The Biosafety Act 2003 becomes law on the 1st, Hwang put in an application for
approval.
9th January, Hwang reported to Park that four of the six SC colonies he had created
were infected with Fungi. Park oversaw implementation of preventative measures but
did not officially report the incident [3].
On the 13th, Hwang’s research became the first to be approved under the new
legislation.
Hwang told Schatten that SCs lines 4 to 7 had become contaminated, but Schatten
urged Hwang to publish anyway because SCs had been produced [4].
June 2005:
Hwang submitted his second ground-breaking paper ‘Patient-Specific Embryonic SCs
Derived from Human SCNT Blastocysts’ [5] to Science.
Schatten and Sung-Il Roh are listed as co-authors.
August 2005:
On the 3rd, Hwang and colleagues announce that they have created a cloned Afghan
hound, Snuppy [28].
As canines produce very immature oocytes many thought that cloning dogs would be
more difficult than human cloning.
Schatten informed Science of about allegations that Sung-Il Roh illegally traded ova,
but insisted that none of the women who donated eggs for their papers were
reimbursed [6].
Schatten broke links with Hwang claiming that he was misinformed about consent
issues surrounding the 2004 paper.
Hwang submitted corrected tables for the 2005 paper.
14
Roh admitted that Hwang had unwittingly used 20 eggs that had been paid for.
Undercover reporters for PD Notebook, a MBC investigative program, endorsed the
accusations and Hwang was forced to concede that he had used eggs that were paid
for and eggs from junior researchers.
December 2005:
MBC questioned the credibility of Hwang's research after obtaining five patientspecific cell line samples from Hwang’s lab. Independent DNA analysis indicated that
one cell line did not match its supposed donor.
Ethical concerns are eased by the conclusions of Hanyang University Hospital’s IRB
on Human Subjects Research that Hwang’s research was not illegal, nor in violation
of the 1964 Helsinki Guidelines that prohibit coercion of research subjects.
~$1,445 was paid for direct expenses, but this had no impact on the validity of the
scientific conclusions and the two junior researchers donated oocytes voluntarily and
without coercion [29].
MBC was forced to apologise for unethical journalism practices following reports
that PD Notebook coerced incriminating statements.
Hwang was once again in the headlines after informing Science that the 2005 paper
included redundant images. Not in the original paper they were submitted by Schatten
as supporting evidence.
The University of Pittsburgh opens an investigation; quickly followed, at Hwang’s
request, by a Seoul National University (SNU) investigation.
Dr Ian Wilmut asked for independent verification of Hwang’s research.
Schatten expressed doubt as to the scientific value of the paper. Asking for his name
to be removed from the paper, Schatten stated that new information and re-evaluation
of data “casts substantial doubts about the paper's accuracy” [30].
15 December, Roh quotes Hwang saying “there are no cloned embryonic stem cells”.
Hwang and Schatten requested their paper be retracted because their data “could not
be trusted”.
Hwang maintained that, although mistakes occurred, patient-matched SCs were
created.
Initial SNU investigations concluded that large proportions of data for the 2005 paper
were fabricated; that data came from two cell lines rather than eleven. Verification as
to whether the two cell lines were clones was still awaited.
15
29 December, SNU reported that there was no evidence that SCs came from patientspecific clones. DNA did not match the patients it was meant to but embryos created
by in vitro fertilization.
Science declared it was moving toward an editorial retraction.
January 2006:
Retraction was confirmed on 4 January 2006.
PD Notebook alleged junior researchers were coerced into donating eggs.
The SNU investigation concluded that both 2004 and 2005 papers were based on
fraudulent data but that Snuppy was a clone and not simply highly inbred.
Hwang apologised, but insisted that his lab was capable of producing patient-specific
SCs and suggested that other researchers may have sabotaged his work.
Hwang claimed his lab could create patient-matched SCs in six months given a
favourable research environment.
The SNU investigation found that Hwang’s “team was in possession of technique[s]
[for] creating cloned human blastocyst[s]”. But, they saw initial cell colony formation
as successful establishment of a cell line, and without any further corroborating
evidence the scientific basis for claiming success was “wholly lacking” [31].
Schatten is declared innocent of research misconduct by University of Pittsburgh, but
they found him guilty of research misbehaviour for not exercising sufficient critical
perspective on collaboration with Hwang [32].
Summary:
Hwang's team possessed neither patient-specific embryonic SCs nor the NT-1 cloned
eSC cell line (it was probably parthenogenic).
The scenario of a rogue scientist swapping cell lines in order to undermine Hwang’
research can not explain the parthenogenetic cell line nor the fabrication of DNA
profiles.
It appears that scientists worked complicitly to deceive those reviewing and
publishing the paper.
Hwang was able to produce, and in possession of, cloned SCNT human blastocysts.
Snuppy was successfully created by SCNT, and Schatten successfully cloned monkey
blastocysts.
16
Appendix B – Compromising Scientific Integrity:
A survey of NIH researchers found that 1.5% would admit to falsifying or plagiarising
data [8]. Such is the pressure to publish that some researchers may start the
publication procedure before they have results to support their assignations –
believing that they can predict the outcome from their preliminary findings. Strong
belief in the general principles of ones science could lead to scientists making rash
judgements; for example, authors of the 2000 Vioxx study failed to inform The New
England Journal of Medicine that several patients had heart attacks while taking the
drug. Additionally, an article on Celebrex in The Journal of the American Medical
Association has been discredited because the authors submitted only 6 months of the
12 months of data they collected [33]. Perhaps worst of all, Paul Kornak altered
patient medical records to facilitate their enrolment in drug trials from which they
should have been omitted due to existing conditions. One patient died and Kornak
was recently jailed for criminally negligent homicide [8].
17
Appendix C – Fame and Pressure:
Stamps dedicated to Hwang, they depict a paralysed man regaining full movement.
Taken from: http://www.sciencemag.org/cgi/reprint/308/5729/1738a.pdf
1.
1.
2.
“The scientist that changed the world - Hwang Woo Suk”
Taken from: http://www.occidentalism.org/?cat=8
2.
South Koreans viewed Hwang as holding the hopes of the world [37]
18
Appendix D – Information Provided By Hwang To Donors:
The information sheets and consent forms used by Hwang have caused much concern
amongst commentators, yet they have proved difficult to obtain. The following
documents were taken from Schatten’s final submission of ‘Patient-Specific
Embryonic Stem Cells Derived From Human SCNT-Blastocysts’ to Science. For
those wishing to assess the standard of the translation the original Korean version of
the consent form has been included. With thanks to Alison Murdoch.
19
Information for Oocyte Donation for Therapeutic Cloning Research
Information for Oocyte Donation for Therapeutic Cloning Research
We would like to request your permission to enrol you as a participant in a research
study. This statement is to provide basic information and knowledge in regard to oocytes donation
for therapeutic cloning research.
Neuronal tissues can be injured by various routes-such as stroke, cerebrospinal injury by
trauma, Parkinson’s disease, Alzheimer, encephalopathy, kinesio-neurosis, cerebrospinal lesion
and more. These injuries may cause death/reduction of working nerve cells/tissues, leading to
permanent brain damages and bodily disorders. Unfortunately, however, effective treatment
methods for these conditions are rare, often with doubtful treatment efficacy. These conditions
have posed significant social and economic burden, not to mention economic and psychological
hardships for patients and their families. If an individual were paralysed from cerebrospinal injuries
by trauma, which may occur especially among a young age group, the duration of medical and
social dependency would span throughout the normal life expectancy. Therefore, the need for
developing a novel and advanced therapeutic method cannot be emphasized too much for these
individuals.
The new therapy for treating these degenerative diseases/ tissue injuries could be found
from the method whereby injured (nerve) cells are replaced by normal (nerve) cells, and stem cells
can be an excellent candidates to be used to replace injured cells. Many scientists are actively
conducting research to understand the characteristics of stem cells. Especially, stem cells called
‘cloned embryonic stem cells’ can re-generate damaged nerve cells when they are grown in large
scale, differentiated to nerve cells, transplanted into a damaged nerve tissue. The ‘cloned
embryonic stem cells’, since they are identical to the damaged cells, are less likely to suffer from
immune rejection, opening a new path to the possible treatment/cure of the various diseases.
Although stem cell research is in its infancy, rapid technical and scientific development
anticipates the actual clinical application in the near future. As one of the global leaders in the field
of stem cell therapy/research, this research institute endeavours to address various diseases by
researching cloned human embryonic stem cell lines through a technique called ‘somatic cell
nuclear transfer (SCNT)‘. The schematics of the SCNT process are described in the figure. The
current research protocol aims to obtain human embryonic stem cell from the SCNT procedures,
differentiate (grow to be a specific type of cells) into neuronal stem cells, and grafted (transplanted)
into patients with neuro-degenerative diseases. The protocol also aims to test the feasibility of the
efficacy and safety of the procedures. For this purpose, voluntary donation of somatic cells and
oocytes is needed to obtain cloned stem cell lines. In order to help you make decisions for your
voluntary participation, we would like to inform and explain in detail the study procedures. You
have your right to refuse to participate, redraw from the study, and cancel the intention to donate
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oocytes at any time prior to the actual donation without any penalty or loss of benefits, which
otherwise you are entitled to.
Information for Oocyte Donation for Therapeutic Cloning Research
Cell fusion
Cloned blastocyst
<Establishment of human cloned embryonic stem cells by somatic cell nuclear transfer (SNCT)
procedure>
This study utilizes human oocytes and somatic cells that are donated by you voluntarily. There
is no direct benefit to you as a result of your participation in this study. No financial reward (in any
form) will be provided. It is hoped that the information obtained from this study may help us better
understand how the stem cells work. Oocytes donated herein can be used for the treatment of
anonymous patient(s), who is (are) not related to you in any way. If oocytes are donated on behalf
of your family member, the designated family member has the priority to receive the donation.
However, any unused oocytes can be used for the treatment of anonymous patient(s), who is (are)
not related to you.
You will be interviewed on your medical history upon enrollment, and several gynecological
tests such as pelvic examination (manual examination of female reproductive organs) and ultra-
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sound examination (ultrasonography) may be given. According to the legal/regulatory requirement,
several laboratory blood tests such as hepatitis test, ADIS test, and syphilis test are required to
determine whether you can participate in the study.
Information for Oocyte Donation for Therapeutic Cloning Research
In order to retrieve oocytes, you will undergo a procedure to induce ‘over-ovulation’ (normal
ovulation is one per menstruation cycle) and collects many oocytes at once. ‘Over-ovulation’ refers
to the procedure to speed up the growth of several ovarian follicles (where an oocyte is nurtured)
by the hormonal injection. More specifically, the hormonal injection starts at 2 ~ 3 days after the
onset of menstruation, and continued for 7 ~ 10 days. Matured ovarian follicles can be seen using
ultrasonography, and doctor(s) will determine the exact timing of extraction procedures.
For the retrieval of oocytes, you may need to undergo general anesthesia (insensibility to
general sensation with loss of consciousness). While you are unconscious, oocytes will be
retrieved via needle under the guidance of ultrasound (a special vaginal probe resembling a
tampon will be inserted into your vagina). During this retrieval process, you shall not feel any
significant pain other than discomfort related to the general anesthetic procedures. The procedures
are conducted typically in the morning. Therefore, you should not eat breakfast since anesthetics
sometimes could cause vomiting in some people. Under the doctor’s observation, you may return
home in 2 ~ 3 hours after the procedure.
We would like to emphasize that there could be unknown risks associated with this procedure.
The major discomfort prior to the donation is related to the blood collection for several preliminary
tests, which may cause pains, bleeding at a lesion site, vein infection or other types of general
infection. In addition, during the over-ovulation procedures, injected hormones may bring known
side effects or symptoms such as headache, nausea, hyper-sensitivity, blood clots, and flare at an
injected site. During the oocyte retrieval, anesthetic agents that are injected for the general
anesthesia may cause side effects such as nausea and vomiting. If you have not been sexually
active, it is possible that ‘hymen’ (thin membrane near the vaginal opening; you may or may not
have it regardless of your sexual history) could be damaged. If you found that you are pregnant or
suspect possible pregnancy during any stages of participation, please inform the researchers as
soon as possible, and stop the participation. Whenever suspicious or unusual symptoms occur,
you may seek the help/medical attention from the physician-in-charge or clinical investigators
immediately. There may be other side effects, although not described above or forecasted. If
present, please report to your physician-in-charge immediately. All the procedures will be explain
to you again when you are scheduled for meeting with initial consultation, and you may ask
detailed questions for all the procedures at any point during this study.
In case you are donating ‘surplus’ oocytes for in vitro fertilization (in IVF procedure), there will
22
be no additional discomfort/procedures other than IVF procedure itself. In any circumstances,
oocytes will not be collected in excessive amount against your intention, and oocytes can be
donated only with the prior written intention/consent for the donation. Other than that, after the
donation, equal right and rules applies to all donors.
Information for Oocyte Donation for Therapeutic Cloning Research
With the successful completion of this project, a new therapeutic cloning method may help
others in the future. Accordingly, the potential benefits/commercial value, including the intellectual
property, may rise from the outcome from this research. However, it is important to inform you that
any immediate medical breakthrough cannot be promised by any means. In addition, we would like
to inform you that you cannot reserve, file, or claim any right on the outcome of the research
activities resulting from this donation.
During and after the study, all the medical records and identifiable information that are
associated with you will be securely protected. If the experimental results are disclosed in
academic journals, textbook, or other form of publications, the identity of the donor will be strictly
classified and protected.
Your signature below indicates your willingness to participate in this study, and your
authorization to gather, use and share with other researchers, both domestic and international,
your private confidential health information under the strict legal guidance on the extent and
method of use or release individual information for research purpose. However, you can withdraw
from the study any time. If you are injured or affected by the side-effects during the course of the
study, or if you have any questions about any aspect of the study, please contact the researcherin-charge and other co-investigators at the number provided in this form. You will always receive
help properly and immediately.
Biomedical and Biotechnology Research Team, Seoul National University Contact Number: 019265-0209
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Appendix E – Oocyte Donation:
The South Korean ethos, in promoting altruistic donation, poses new questions for
research participation. Excess IVF embryos are seen as the most ethically acceptable
source of oocytes - whether they are suitable for all research is a controversial
question. Excess IVF embryos currently have ethical and legal advantages for use in
SC research because the woman, having given clinical consent for the IVF procedure,
is a patient. As a patient she is able to give research consent for any excess embryo’s
to be used for research. Hwang required unfertilised oocytes, and many indicate that
‘fresh’ oocytes from younger donors are most productive. To obtain ‘fresh’ oocytes
Hwang enrolled patient family members, as akin to organ donation. Many suggest that
oocyte donation and organ donation are equivalent. This maybe true when, and if, SC
therapy becomes clinically viable. However, clinical viability is unproven and the
argument invalid. Organ donation from family is ethically comprehensible because
donors gain personally from the patient’s recovery. Will family feel a duty to donate
to SC research without any foreseeable benefit? Research donors must be made
acutely aware of the gulf between research and therapy; currently, family maybe more
ethically vulnerable than altruistic donors.
The use of altruistic donors raises its own ethical and consent problems. Women
donating eggs purely for research, altruism, are hard to classify as patients because the
procedure go against their best interests. The women expose themselves to not
insignificant risks only for the presumed future good of others. Studies put the risk of
ovarian hyper-stimulation syndrome following oocyte procurement from 0.1% up to
10%. Altruistic donors, especially with regard to organ donation, have their motives
severely scrutinised and some societies find that such donations are ethically and
practically difficult. With organ donation ethical concern is raised by recipients
feeling indebted to donors and/or the possibility of donors expecting some form of
reward.
Altruistic donors to research could be treated as research subjects. However, research
subjects usually partake knowing that the research results could be of direct benefit to
themselves – this is extremely unlikely for SC research. Additionally, the
classification of research subject may not be adequate because the research is not in
26
the procedure the donor undergoes but in the use of their donated tissue. Informed
consent for research subjects focuses on the research - the post-procurement details
that have no risk for the subject.
Information sheets and consent forms used by Hwang dealt little with the risk of
procurement [Appendix D], though this is the only significant risk undertaken. Risk
being undertaken to provide raw materials for research requires new ideas for consent.
Magnus and Cho recommend the term ‘Research Donor’ be used for those undergoing
not insignificant risk in donating [21]. A delicate position because risk will vary with
the type of donation but equivalent rights should be available to all donors. With
regard to donor rights, many advocate the creation of donor databases. Such facilities
would allow donation to be properly regulated and protect donors from taking part in
‘incompatible’ research projects.
The website www.ovadonation.or.kr is worrying because the details regarding
donation are unclear, at least to the author at this time. Will the website act as a
depository which licensed researchers can use to approach women willing to donate,
or will a private ‘oocyte procurement’ company contact registered women? The
former option could prevent women donating more than the legal number of times
and ensure that a suitable time-space is left between procedures. Women, once
contacted, would become ‘research donors’ and go through IRB approved informed
consent procedures. The latter possibility raises concern that women may be
exploited. Would women decide which research benefits from their oocytes? Will
oocytes be ‘sold’ for profit or reproduction? The website highlights the need for
regulation of not just research but tissue donation. Regulation in this area may take its
lead from the UK where the fertility watchdog is planning to revise laws to allow
oocyte donation for research.
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Appendix F – Journals:
Journals chronicle original developments in science. If research has scientific value it
is outside the remit of journals to censor. Often it is unclear whether research is
unethical or illegal because the answers are not mutually exclusive to the context.
Whether it was unethical of Hwang to use eggs from junior researchers depends on
Hwang’s involvement and the South Korea ethos. Additionally, there was little
precedence for the case because such a situation had never arisen before. Previously
researchers have taken part in their own research and this is now seen as unethical.
However, this was donating to rather than participating in research, and even now
there is division on whether Hwang broke ethical protocol.
Journals could assess a paper’s ethics; though this problematises what ethical means.
If illegal, is something by necessity unethical? Should an American journal publish
research that though legal/ethical in its country of origin is illegal/unethical in
America? Most argue that ethical and legal considerations should come from the
country of origin rather than publication. The Hinxton Group encourages journals to
“require a statement from scientists that their research conforms to local laws and
policies” [25]. Journals and peer-review are concerned with scientific originality. If
excessive time was spent debating a paper’s ethical quality originality could be lost
and this would be disadvantageous to both journal and author. Additionally, results of
the NIH survey suggest that peer-review may be deficient because 12.5% of over
3000 respondents admitted to ‘looking the other way’ when colleagues used flawed
data [8].
28
Appendix G – Publishing, Credit Where Credit Is Due:
The link between publications and funding means it is common practice for anyone,
even vaguely, involved with research to be a co-author. Additionally, lead authors
may not be the most significant person in the research; as exemplified by the current
case surrounding ‘Dolly’ which has striking similarities to Schatten being secondauthor on Hwang’s 2005.
For the last ten years, Dr Ian Wilmut has been widely credited with the successful
creation of ‘Dolly the sheep’ via SCNT-cloning. However, a recent legal hearing
forced him to admit that he was only the lead author because of a prior agreement and
that Professor Keith Campbell deserved 66% of the credit [34]. Additionally, it
appears that much of the work was done by two technicians, Bill Ritchie and Karen
Mycock, who because of their positions were not seen worthy of co-authorship –
merely being acknowledged at the end of the paper [35].
It is obviously advantageous for scientists to author/co-author as many publications as
possible; thus, driving the trend for ever increasing numbers of authors. There were
15 and 25 authors respectively on Hwang’s 2004 and 2005 papers. Though most were
probably involved, should they all be authors? Research has two components: theory
and practice. It is no longer the case, given the high degree of specialisation in
modern science, that these are approached by the same person. Both are integral to
success but there are vast differences between academic theory and technical
expertise - it may be valuable to draw such distinctions within papers. Journals are
considering making authors detail their involvement in projects so they can ascertain
whether authorship is valid and assign responsibilities. Journals should ensure that by
being an author one accepts full-responsibility for having over-seen all data and
drawn the conclusions. It may also be advantageous to limit the number of authors,
thus preventing academic-hierarchies from influencing authorship.
29
Bibliography:
1. Hwang's 'Guardian Angel' Owes Us an Explanation – Digital Chosunilbo
http://english.chosun.com/w21data/html/news/200601/200601180028.html
2. Hwang et al, Evidence of a Pluripotent Human Embryonic Stem Cell Line
Derived from a Cloned Blastocyst, Science (303), 1669-1674
3. Roh Aide Caught in Stem Cell Scandal – The Korea Times
http://times.hankooki.com/lpage/nation/200512/kt2005121817312911990.htm
4. Schatten Deeply Implicated in Hwang Fraud: Witness
http://english.chosun.com/w21data/html/news/200602/200602160014.html
5. Woo-Suk Hwang et al, Science (308); 1777-1783
6. http://theseoultimes.com/ST/?url=/ST/db/read.php?idx=2698
7. Mario Biagioli, Judith Crane, Pamela Derish, Mark Gruber, Drummond
Rennie and Richard Horton (1999): CSE task force on authorship (draft white
paper) http://www.councilscienceeditors.org/services/atf_whitepaper.cfm
8. Peter N Spotts: ‘Laboratory ethics: What makes some scientists cheat?’,
http://csmonitor.com/2005/1222/p02s01-stss.html (2005)
9. D. E. Barnes, L. A. Bero. Jama 1998: 279(19); 1566-70 - Why review articles
on the health effects of passive smoking reach different conclusions
10. Normitsu Onishi (22 January 2006): ‘In a Country That Craved Respect, Stem
Cell Scientist Rode a Wave of Korean Pride’;
http://www.nytimes.com/2006/01/22/science/22clone.html?ex=1146456000&
en=d9d607e5faca717d&ei=5070
11. Mike Weisbart, The Korea Times (2006):
http://times.hankooki.com/lpage/opinion/200603/kt2006030616250354190.ht
m
12. http://en.wikipedia.org/wiki/Hwang_Woo-Suk
13. Shanghai Star: http://app1.chinadaily.com.cn/star/2005/1229/vo18-4.htm
14. Kim Tae-Gyu (2005), The Korea Times – Hwang Targets AIDS Cure
http://times.hankooki.com/lpage/200510/kt2005101817143910440.htm
30
15. Publications – Korean Bioethics Association
http://www.koreabioethics.net/pub.htm
16. Kim Cheong-won, The Korea Times (2006):
http://times.hankooki.com/lpage/nation/200602/kt2006020218595910510.htm
17. Magnus, D and Cho,M (2006) The American Journal of Bioethics 6(1):W23
18. Jon Merz (2006) summary of a Korean Herald article :
http://www.irbforum.com/forum/read/2/113/113?PHPSESSID=46cedf2f80a28
3bb41c3ae467abb65fc
19. Jung and Hyun: AJOB (2006)
20. Gottweis, H and Triendl, R: ‘South Korean policy failure and the Hwang
debacle’, Nature Biotechnology (2006); 24 (2), 141-143
21. Magnus, D and Cho, M: Issues in Oocyte Donation for Stem Cell Research,
Science (2005), 308 1747-1748
22. Editorial: “Study shows bioethics awareness lacking”, Dong-a Ilbo, East Asia
Daily, Seoul 25 November 2005
23. Glenn McGee, Editorial Retraction (2006) The American Journal of Bioethics
6(1):W33 http://bioethics.net/journal/j_articles.php?aid=913
24. Robert J. Lifton: ‘THE NAZI DOCTORS: Medical Killing and thePsychology of
Genocide’ ISBN 0-465-09094 © 1986
25. Hinxton Group: Consensus Statement (2006)
http://www.hopkinsmedicine.org/bioethics/finalsc.doc
26. Jung and Hyun: AJOB (2006)
27. Gottweis, H and Triendl, R: ‘South Korean policy failure and the Hwang
debacle’, Nature Biotechnology (2006); 24 (2), 141-143
28. Lee B. C. et al. Nature 436, 641; 2005
29. http://www.sciencemag.org/sciext/hwang2005/science_statement.pdf
30. http://www.mindfully.org/Health/2005/Schatten-Stem-Cell14dec05.htm
31. Jane Parry, ‘University clears scientist of misconduct but says his conduct was
misbehaviour’ BMJ (2006); 332:382
31
32. Text of the Report on Dr. Hwang Woo Suk:
http://www.nytimes.com/2006/01/09/science/textclonereport.html?pagewanted=3&ei=5070&en=a73f 517617a886e6&ex=1137
560400
33. Julie Bosman: ‘Reporters Find Science Journals Harder to Trust, but Not Easy
to Verify’, New York Times (February 13, 2006)
34. Vogel, G and Marshall, E: ‘Bias Claim Stirs Up Ghost of Dolly’, Science
(2006); 311, pg1539.
35. Sample, I: ‘Who really made Dolly? Tale of British triumph descends into
scientists' squabble’, The Guardian (2006)
http://www.guardian.co.uk/science/story/0,,1728626,00.html
36. Korea's Cloning King in Stem Cell Breakthrough
http://english.chosun.com/w21data/html/news/200505/200505190028.html
37. Dr Stephen Minger (2006): The Fall Of A Scientific Rock Star
http://news.bbc.co.uk/1/hi/sci/tech/4599974.stm
38. Charles Scanlon (2006) Korea's national shock at scandal
http://news.bbc.co.uk/1/hi/world/asia-pacific/4608838.stm
39.
Select Committee on Science and Technology Tenth Report
http://www.publications.parliament.uk/pa/cm200304/cmselect/cmsctech/399/3
9912.htm
40. Insoo Hyun and Kyu Won Jung, Letter to the Editor Concerning Oocyte and
Somatic Cell Procurement for Stem Cell Research (2005), The American
Journal of Bioethics 5(6):Wxx
41. Julian Savulescu and Rhodri Saunders, ‘The “Hinxton Group” Considers
Transnational Stem Cell Research’, The Hastings Centre Report (May/June
2006)
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