[GRG] NewAbs: Comparison of iPSC’s with SCNT Therapies

To Members and Friends of the Los Angeles Gerontology
Research Group:
      SCNT better than iPSC’s.  — Steve
Coles

“Cloning Offers Intriguing Stem
Cell-Making Tips”

by
Cynthia Fox
Cloning diagram.
(Source: Wikimedia/Belkorin)
Monday, July 28, 2014; (Bioscience and Technology) — Two recent
studies ­- one human, one mouse -­  have found cloning creates
better pluripotent stem cells than the Nobel Prize-winning induced
Pluripotent Stem Cell (iPSC) method.
    Cloning involves fusing an old cell (or nucleus) with
an egg cell and letting the egg reprogram and rejuvenate it -­  just
as it reprograms and rejuvenates mature sperm during conception. It is a
physiologic process. However, the more artificial iPSC method involves
genetically tweaking four genes.
    “Based on our recent study, oocyte [egg] cytoplasmic
factors induce reprogramming of somatic cells into superior quality
embryonic/pluripotent state than conventional iPSC approaches,” the
author of one of the studies, Shoukhrat Mitalipov, told Bioscience
Technology in an E-mail.
    As if choreographed, a perfectly timed, third study
came out last week supporting the conclusions. The third study
identified, in egg cells, one protein that may help explain the egg’s
aforementioned super-powers.
    “A very nice study,” Mitalipov said of the third
paper. Mitalipov is Director of the Center for Embryonic Cell and Gene
Therapy at the Oregon Health and Science University (OHSU). Earlier, he
was the first scientist to clone human cells. “It makes sense to
understand and mimic oocyte factors for reprogramming so we can produce
better iPSC’s.”Cloned stem cells epigenetically
superior
    Mitalipov’s paper, published in

Nature

, was the first to compare human pluripotent cells (embryonic stem,
or ES, cells) from IVF clinic embryos to those made via cloning, and via
the iPSC method -­ “isogenic” cells from the same individual. Noting that
ES cells (which form all somatic tissues of the body) from IVF clinic
embryos are the “gold standard,” they compared the cells in many
ways.
    There were no statistically significant de novo
CNVs (copy number variations) caused by reprogramming, the paper noted.
CNV’s are abnormal swaths of DNA sometimes linked to cancer.
    But there was a significant, eight-fold greater number
of methylation sites in iPSC’s -­ carried over from parent cells -­ than
in stem cells made via cloning. Indeed, the cloned cells resembled “gold
standard” ES cells in epigenetic methylations patterns (which determine
what genes turn on) more than iPSCs.
    Furthermore, the corresponding transcriptional
signatures (gene expression patterns) of the cloned stem cells were more
similar to “gold standard” IVF ES cells than to iPSC’s. That is,
turned-on or expressed genes were more alike between ES and cloned cells
(in line with the above methylation data).
   “Transcription factor-based reprogramming (the iPSC method)
is associated with incomplete epigenetic reprogramming,” the paper
continued. “In contrast, the same somatic cells reprogrammed by SCNT
(Somatic Cell Nuclear Transfer, or cloning) displayed epigenetic and
transcriptional signatures remarkably similar to those of IVF ESC
controls…An explanation for this more effective reprogramming by SCNT is
that the ooplasm provides ‘physiologic’ levels of reprogramming
factors…It has been suggested that oocyte factors rapidly demethylate the
somatic genome…Clearly elucidation of oocyte-based reprogramming
mechanisms will support the development of improved reprogramming
methods.”
    The study also noted that while CNV numbers ­ which
can influence tumorigenicity­ were not statistically different, the team
did not study point mutations and other potential cancer
influences.Cloned stem cells may be
genetically superior
    But a study appearing in an abstract at the June ISSCR
meeting­ and as a paper in an earlier

Stem Cell Reports­ did find more (potentially cancer-causing)
point mutations in the iPSC method than in cloning. Abe Masumi, director
of the National Institute of Radiological Sciences in Chiba, Japan, found
there was “an obvious difference in the frequency and mode of point
mutations” between iPSCs and cloned cells, with more appearing in iPSC’s,
he said in an interview with Bioscience Technology at the ISSCR.
The study was done with mouse cells from the same embryos. He also found
“a large number” of iPSC point mutations were not pre-existing, but de
novo, and that there was heterogeneity of point-mutation profiles in
identical iPSC’s. “The heterogeneity of the point mutation patterns in a
single iPSC (identical subline) reflects the history of the emergence of
each mutation.”
    By E-mail later, Masumi added: “Although a large
number of point mutations have been identified in iPSC genomes by several
groups thus far, no relation has been found between such point mutations
and any functions. In-depth and large-scale analyses should be required
for addressing this issue, e.g., relation between genetic aberrations and
the differentiation-defective cells described by Dr. Yamanaka.”
    Masumi was referring to Shinya Yamanaka, the
University of Kyoto scientist who won the Nobel Prize for his creation of
iPSCs. At the ISSCR, Yamanaka presented evidence that it may be possible
to isolate the iPSC method’s reprogramming-defective cells, leaving
behind more healthy iPSC’s.Is the egg already yielding
secrets?
     In the meantime, in the July 17th

Science

, another group has found a critical reprogramming protein in the
egg. The team of the University of Michigan’s Jose Cibelli, a cloning
pioneer, reported that overexpression of ASF-1A, a histone remodeling
chaperone enriched in the Metaphase-II human oocyte, is necessary to
reprogram cells. “Our report underscores the importance of studying the
unfertilized MII oocyte as a means to understand the molecular pathways
governing somatic cell reprogramming,” Cibelli’s paper
concluded.
    A key reason to improve iPSC’s with cloning tips,
rather than switch to cloning: cloning uses precious human eggs. The iPSC
method can theoretically give adults uncontroversial supplies of their
own, genetically identical pluripotent stem cells.
   

Other papers finding cloned stem cells superior to iPSC’s include an
April 2014 Stem Cell Reports study by University of California
stem cell researcher Yang Xu; a January 2014 Cell Stem Cell study
by the National Institute of Biological Sciences’ Sharong Gao; and a
January 2013 Cell Research study by Jinsong Li.
Topics:

Human Studies

Stem Cells

Health

Exclusive

L. Stephen Coles, M.D., Ph.D., Cofounder
Los Angeles Gerontology Research GroupE-mail: scoles@grg.orgE-mail:
scoles@ucla.edu

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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