[GRG] NewAbs: Human Stem-Cell Clock Reset to ‘Zero’

To Members and Friends of the Los Angles Gerontology
Research Group:Pristine
hiPSC’s are a major stepping stone toward our agenda. What took us so
Should we throw more money at the problem or do we need more smart
people? Or both?
— Steve Coles

“Human Stem-Cell Clock Reset to
‘Zero'”byKevin Mayer

In this 3-D
rendering of confocal images, human embryonic stem cells (hESC’s)
are identified with a pluripotency marker (NANOG, in
DNA methylation
(red) is
reduced in reset cells.
[Wolf Reik and Gabriella Ficz, Babraham Institute]
September 12, 2014; (Genetic Engineering News) —  Adult
stem cells are routinely taken back to early developmental states —
but not all the way back, not to the very start of human development.

Yes, under the manipulations of scientists, these cells can typically
induced to pluripotency, the ability to follow different developmental
Yet, these cells are not blank slates, i.e., they are not


They retain biases toward particular cell fates and tissue
types, complicating
their use in therapeutic applications, such as regenerative
    “Almost zero” stem cells naturally vary.
Their developmental clocks
are not quite synchronized; their developmental biases differ in
Such variability has been built into stem-cell research, making it more

difficult to reconcile results from different studies.
    All such complications may be swept aside, or
diminished, now that scientists from the Wellcome Trust, the
Babraham Institute, and the European Bioinformatics Institute

have found a way to reset human pluripotent stem cells to a pristine

state — a developmental state equivalent to cells found in an embryo

before it implants in the womb ([7 ­ 9] days old).
    The scientists achieved for human cells — a feat
previously limited
to cells from mice and rats. Specifically, the scientists reverted
human cells to ground-state pluripotency. The scientists, however,

could not use the approach that has proven so reliable with mouse
cells. Although mouse cells respond to a protein called Leukemia
Inhibitory Factor (LIF), entering a state of naive pluripotency,
human cells did not.
    To overcome this difficulty, the researchers took a
new approach.
They used reprogramming methods to express two different genes,
NANOG and KLF-2. These genes, which needed to be expressed,
but only briefly, caused the network of genes that controls the cell

to “reboot” and induce the naive pluripotent state.
    This finding appeared September 11th in the journal
Cell, in an
article entitled, “Resetting Transcription Factor Control Circuitry

toward Ground-State Pluripotency in Human.”
    “Reset cells self-renew continuously without ERK
signaling, are
phenotypically stable, and are karyotypically intact,” wrote the

authors. “They differentiate in vitro and form teratomas
in vivo.
Metabolism is reprogrammed with activation of mitochondrial
respiration as in ESC. DNA methylation is dramatically reduced, and
transcriptome state is globally realigned across multiple cell
    The reset human stem cells showed a loss of methyl
throughout the genome. Such marks, which accumulate during cell
development, are a form of epigenetic memory. By removing such
marks, the new procedure essentially wipes away epigenetic
memories, pushing the cells back to a more permissive state.
Without an epigenetic memory of their previous lineages, the cells
effectively achieved “blank slate” status and gained
potential to become any adult cell.
    “Our findings suggest that it is possible to
rewind the clock
to achieve true ground-state pluripotency in human cells,” said

Prof. Austin Smith, Director of the Wellcome Trust — Medical
Research Council Stem Cell Institute. “These cells may represent

the real starting point for formation of tissues in the human
embryo. We hope that in time they will allow us to unlock the
fundamental biology of early development, which is impossible to
study directly in people.”
    The discovery may pave the way for the production of
patient material for translational medicine. Reset cells mark a
significant advance for human stem-cell applications, such as drug
screening of patient-specific cells, and are expected to provide
reliable sources of specialized cell types for regenerative tissue


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


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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