| Review Article |
Open Access |
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| Use of hESC Lines by CIRM Grantees: The Value of Embryonic Stem Cell
Research Oversight (ESCRO) Committees |
| Rohun Patel and Geoffrey Lomax* |
| California Institute for Regenerative Medicine, San Francisco, California 94107, USA |
| *Corresponding author: |
Dr. Geoffrey Lomax
California Institute for Regenerative
Medicine
San Francisco, California 94107, USA
E-mail: glomax@cirm.ca.gov |
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| Received October 14, 2011; Accepted November 12, 2011; Published November
14, 2011 |
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| Citation: Patel R, Lomax G (2011) Use of hESC Lines by CIRM Grantees: The
Value of Embryonic Stem Cell Research Oversight (ESCRO) Committees. J Stem
Cell Res Ther 1:107. doi:10.4172/2157-7633.1000107 |
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| Copyright: © 2011 Patel R, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Introduction |
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| Human embryonic stem cell (hESC) research occupies an
exceptional place in science because governments and funding
organizations have adopted unique polices to influence research
conduct [1]. These policies often extend to the research tools themselves,
hESC lines. For example, the U.S. NIH maintains a registry of hESC
lines approved for use in research it funds. The U.K. Stem Cell Bank
employs a vetting procedure to ensure deposited lines conform to
specific requirements. |
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| As a consequence the use of specific hESC lines is a topic of
ongoing international interest because utilization patterns serve as
a research and evaluation tool. For example, previous studies have
examined utilization patterns to evaluate the impact of state-based
research programs [2]. McCormic et. al. examined distribution rates
and patterns of hESC line utilization as an indicator of state research
capacity [3]. Karmali et al. [4] examined the use of hESC lines not eligible
for NIH funding as an indicator of the efficacy of state-funded stem cell
research programs [4]. These studies quantified transfers of selected
hESC lines or reported surveys of hESC line requests as indicators or
proxies to support their analysis. |
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| In this article, we build on this literature by quantifying the
utilization of specific hESC lines based on reports from CIRM grantees.
These reports provide an added level of resolution allowing us to (1)
elaborate on findings from previous studies and (2) evaluate the efficacy
of CIRM-specific policies for research review and oversight. |
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| CIRM policies for research review and oversight |
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| The California Institute for Regenerative Medicine (CIRM) was
established, in part, to support research not eligible for federal funding
in the United States. In 2006, the Institute promulgated regulations
consistent with the National Academies' Guidelines for Human
Embryonic Stem Cell Research. The NAS Guidelines are intended to
support the responsible and ethical conduct of research not eligible for
federal funding [5]. The guidelines recommend institutions establish
human embryonic stem research oversight (ESCRO) committees to
provide oversight for the use of hESC lines not otherwise covered by
the NIH guidelines. |
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| CIRM has incorporated the NAS Guidelines as formal regulations
applicable to all CIRM-funded research. The CIRM regulations allow
grantees to utilize human embryonic stem cell lines that conform to
standards for acceptable derivation [6]. |
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| To be acceptably derived any one of the following criteria must be
met:1 |
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| 1. Be approved for use in NIH-funded research after March
2009 (NIH Registry Lines) [http://stemcells.nih.gov/research/
registry/] |
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| 2. Be derived by a CIRM-funded grantee in accordance with
CIRM requirements (CIRM-derived lines) [http://www.cirm.
ca.gov/files/reg/pdf/Reg100080_SM_Acct_Standards.pdf] |
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| 3. Be determined to meet CIRM standards by anESCRO
committee (ESCRO approved lines) |
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| 4. Be NIH-approved prior to 2009 but not currently listed
in the NIH Registry (NIH Registry prior to 2009) [http://
stemcells.nih.gov/staticresources/research/registry/PDFs/
FormerRegistry.pdf] |
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| 5. Be deposited in the UK Stem Cell Bank (UKSCB lines) [http://
www.ukstemcellbank.org.uk/stemcelllines.cfm] |
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| CIRM grantees document their use of specific hESC lines in annual
progress reports. Based on these reports, hESC lines may be classified
according to the regulatory / policy criteria above. Criterion number
three, ESCRO approved lines, is of particular interest with regard to
evaluating the efficacy of policies for research review and oversight.
CIRM and other state-based stem cell research programs require ESCRO
oversight of most funded protocols. Further, ESCRO committees
report hESC provenance review to be a major programmatic activity.
For example, 75% (n=21/28) of ESCRO committees responding to a
national survey by the Intestate Alliance on Stem Cell Research http://
iascr.org/docs/2011/ESCRO%20committee%20survey%202011.pdf reported provenance review to be a responsibility. For purposes of
evaluating policy efficacy, it is helpful to understand the role ESCROs
play in enabling research that would otherwise be ineligible for federal
funding. |
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| 1Lines derived in accordance with the Japanese National guidelines, Canadian
Institutes for Health Research guidelines, UK Human Fertilization and Embryology
Authority (UK HFEA) license or Australian Research Involving Human Embryos Act
license are also acceptable for use. However, no lines direved in accordance with
the Japanese, Canadian or Australian policies were utilized by CIRM grantees and
UK HFEA lines were also deposited in the UKSCB. |
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| Methods |
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| CIRM's reporting forms request grantees to identify all hESC lines
used in Institute-funded research during the previous year. Reporting
is performed either by choosing from a list of 39 common hESC lines and/or by self-entering the names of lines not included on the list. As
of August 2011, CIRM had 238 active awards that met the inclusion
criteria for this analysis. To be included: (1) the grantee must have
submitted one or more annual progress reports and (2) the award
must be a research grant (training, planning and facilities grants were
excluded). 97 grants (41%) reported utilizing one or more hESC lines. |
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| All hESC lines used in these 97 grants were then coded according to
their regulatory status at the time of analysis. Any particular line could
be included in one or more of the following regulatory categories:
(1) Current NIH Registry Lines, (2) CIRM derived lines; (3) ESCRO
approved lines, (4) NIH Registry prior to 2009, or (5) UKSCB lines. |
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| Any particular line could be included in one or more regulatory
category, but for reporting purposes, each was assigned to a unique
category based on a hierarchy. Any given line was assigned to the
lowest possible numerical category. For example, H9 was approved for
use by NIH in 2001 (category 4), and it was subsequently approved
for use after December 2009 (category 1). Therefore, H9 is assigned
to category 1. Similarly, CIRM grantees have reported the derivation
of 17 lines (category 2). Seven of these lines are NIH registered, so
they were assigned to category 1. This hierarchical approach allows
us to distinguish between research eligible for federal funding,
predominantly NIH. |
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| Results |
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| 138 unique hESC lines were utilized in the 97 grants meeting our
inclusion criteria. Seventy-five percent of the hESC lines utilized
(n=103) were not eligible for federal funding at the time this analysis
was conducted - regulatory status 2-5. Table 1 reports the utilization of
lines according to their current regulatory status. |
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| The cross-sectional nature of this analysis should be recognized.
For example, grants involving the ten lines in category 4 (NIH Registry
prior to 2009) were awarded prior to the Presidential Executive Order
of March 2009. Therefore, they would have been eligible for federal
funding at the time of the award. If one were to consider eligibility
at time of funding then, sixty-seven percent of the lines utilized were
ineligible. |
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| The majority of lines used (n=70) by CIRM grantees were
determined to meet CIRM standards by an ESCRO committee. This
figure is double the number of currently NIH-eligible lines being used.
In addition, sixteen of the hESC lines used were derived and utilized by
CIRM grantees. Of these sixteen, seven are included in the current NIH
registry (Table 2). |
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| In terms of intensity of utilization, H9 and H1 are the most
frequently utilized lines involved in 77 and 53 studies respectively.
Current NIH registry lines account for seven of the top ten lines
utilized. |
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Table 1: CIRM Grantee hESC Utilization by Regulatory Status. |
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Table 2: hESC Lines Most Frequently Used by CIRM Grantees. |
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| Discussion |
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| Consistent with previous studies, we observe hESC lines derived at
WiCell Research Institute (H series) and Harvard University (HuES)
are the most frequently utilized. This intensity of utilization may be
attribute to their NIH eligibility status, well developed material transfer
agreements, policy decisions to support their distribution through the
National Stem Cell Bank and their resulting scientific utility. |
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| We also observe an ongoing research investment in hESC lines
approved by NIH prior to 2009 but not currently listed in their Registry.
These lines include HSF1, HSF 6 and HES1-5 used in 13, 11 and 20
protocols respectively. Under NIH policy, grantees may continue to
utilize lines in grants awarded before March 2009, but such use would
eventually be phased out. CIRM policy allows for the use of all current
and formerly registered NIH lines. We believe this approach serves to
support research programs that have made a sizable investment in lines
approved under the former policy. |
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| 75% of hESC lines utilized by CIRM-funded researchers are
not eligible for use in NIH-funded studies. Due to their timing and
methodological limitations, previously cited studies were not able to quantify
this proportion. In addition, CIRM-funded researchers derived 17
hESC lines. These data suggest state-based research programs serve to
expand the scope of studies and the supply of hESC lines. |
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| The data also illustrate the importance of embryonic stem cell
research oversight (ESCRO) committees in evaluating the provenance
of hESC lines. The majority of hESC lines utilized by CIRM grantees
are not currently or previously approved by NIH or deposited in the
UKSCB. Such lines must be evaluated against criteria consistent with
the National Academies' Guidelines for Human Embryonic Stem Cell
Research. Given there are over 1000 lines (ISSCR accessed 09/07/2011)
identified in the UMASS International Stem Cell Registry, there is an
ongoing need to evaluate the provenance of hESC lines to ensure they
are derived according to consensus standards. |
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| The ability of researchers to utilize ESCRO committees is critical
for allowing immediate access to lines not otherwise approved by
other regulatory bodies. CIRM-funded researchers have suggested this
access serves to fill knowledge gaps in the field of human pluripotent
cell biology. |
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| Acknowledgements |
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| We thank Bill Gimbel, Kelly Shepard and Steve Torrence for their efforts to
provide the underlying data to support this analysis. |
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| References |
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- Lomax G, McNab A (2008) Harmonizing standards and coding for hESC
research. Cell Stem Cell 2: 201-202.
- Levine AD (2011) Policy uncertainty and the conduct of stem cell research. Cell
Stem Cell 8: 132-135.
- McCormick JB, Owen-Smith J, Scott CT (2009) Distribution of human
embryonic stem cell lines: who, when, and where. Cell Stem Cell 4: 107-110.
- Karmali RN, Jones NM, Levine AD (2010) Tracking and assessing the rise of
state-funded stem cell research. Nat Biotechnol 28: 1246-1248.
- NAS (2010) Final report of the National Academies human embryonic stem cell
research advisory committee and 2010 amendments to the National Academies'
Guidelines for Human Embryonic Stem Cell Research. Washington, D.C.,
National Research Council (U.S.).
- Lomax GP, Hall ZW, Lo B (2007) Responsible oversight of human stem cell
research: the California Institute for Regenerative Medicine's medical and
ethical standards. PLoS Med 4: e114.
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