Science Highlights – October 2017

Circadian Rhythms in the Spotlight

The 2017 Nobel Prize in Physiology for circadian rhythm discoveries is exciting news for Bedford Research.

Almost a decade ago, Bedford Research scientists discovered circadian rhythm genes were turned on as early as three days (the 8-Cell stage) after a human egg was activated by sperm (1).

Although circadian rhythms were discovered over a century ago, their importance and their molecular basis is a fast-growing field in the past 20 years.  Bedford Research scientists became aware of circadian rhythm genes while researching ways to improve the efficiency of developing therapeutically valuable stem cells from human eggs activated without sperm (parthenotes).


Circadian Rhythm:  a behavior that repeats every 24 hours


The new Nobel Laureates, Jeffrey Hall and Michael Rosbash of Brandeis University, and Michael Young of Rockefeller University, simultaneously discovered a protein, “PER,” in fruit flies over 30 years ago that increased after dark and decreased during the day.  The key finding was that although the rise and fall of “PER” was entrained by cycles of light and dark, the circadian pattern persisted even after the fly was kept in solid darkness for several days.  Hence, production of the protein wasn’t directly stimulated by light exposure, but had become its own internal, circadian mechanism.

We now know that all cells are regulated by circadian rhythms, a fundamentally important process that controls both behavior, e.g. sleep, and cellular processes, such as release of hormones.

Mammalian circadian rhythm genes are different from those in fruit flies, and were discovered by several investigative teams in the 1990’s:

Takahashi and colleagues identified the mammalian gene, CLOCK, as essential for normal circadian rhythms. Mammalian cells have three “PER” genes:  PERIOD 1, -2, -3, plus two forms of a gene, CRYPTOCHROME discovered by Sancar and colleagues to form a complex with PERIOD.

Hogenesch, Ikea and Nomura discovered ARNTL (also known as BMAL), which was shown to form a complex with CLOCK by Weitz and colleagues, including Fred Davis, Bedford Research Advisor.

The picture has now emerged of an elegantly simple feed-back loop that takes 24 hours to complete, is thought to control about 12% of mammalian genes, and is maintained by stimuli from the supra-chiasmatic nucleus in the hypothalamus.


Core circadian oscillators:  CLOCK/ARNTL stimulates PER/CRY which feed-back inhibits CLOCK/ARNTL, which decreases PER/CRY allowing CLOCK/ARNTL to increase again, in a 24 hour cycle.


Bedford Research scientists, however, have more recently reported(2,3) that approximately 70% of key regulatory genes expressed at high levels at the 8-Cell stage of development are circadianly controlled(4), and that in contrast to the 8-cell stage, the core circadian oscillators in human stem cells in long term culture are silent, calling into question the normality of their responses during experiments.

There is a pressing need to support circadian rhythms during the derivation, long term culture and study of human stem cells.  Bedford Research scientists began to develop such methods a decade ago, the importance of which is supported by this year’s Nobel Prizes.  Hearty congratulations to Jeffrey Hall, Michael Rosbash and Michael Young.

(1) JARG 26:187; (2) JARG 27: 265; (3) SCD 25:160;    (4) circadb.hogeneschlab.org

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Job Opening: Scientific Director

The Bedford Research Foundation is seeking a scientific director to lead its program to derive parthenogenetic stem cells from unfertilized human eggs.  Experience with human eggs and stem cell derivation is required.  Proven success in obtaining grant funding and a strong publication record are also required.

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Bedford Research Foundation 2016 Newsletter

2016 has been a huge year for the Foundation’s work, read about it in the 2016 Newsletter.

The latest headlines include a chronicle of our milestones over the past 20 years, news about our stem cell program with gene editing, Universal Mouse Model Stem Cell Resistant To HIV Infection, our prostate disease research, a new staff member, a new board member and more exciting new growth at our Bedford office.

Bedford Research Foundation 2016 Newsletter (PDF)

On twenty years of progress: Letter from our director

With the help of generous philanthropists and medical collaborators, Dr. Ann Kiessling founded the Bedford Research Foundation in 1996 to address a research need that could not be federally funded — how to help men infected by HIV through tainted blood transfusions have children without infecting their wives and babies. The first “Special Program for Assisted Reproduction,” or SPAR baby was born in 1998.  Ryan Schlosser, now 16 years old, visited the Bedford Research lab last summer. As of September, 2015, 246 babies SPAR babies have been born with all moms and babies testing negative for HIV.Ann Baby Ryan

In 1999, BRF responded to a new research need that could not be federally funded — the derivation of stem cells from unfertilized human eggs.  Bedford Research scientists spear-headed the world’s first ethics advisory board and medical team charged with the task of developing the “gold standard” for women volunteering to donate their eggs for research.

To be clinically feasible, at least 10% of activated, unfertilized human eggs must successfully develop into stem cells.  When initial experiments failed to reach this goal, BRF scientists collaborated with colleagues in Greece to discover what genes must be activate in unfertilized eggs to reach the 10% efficiency needed.  Our results, published in three landmark reports, have led to the information needed to resume the research.  As described in the cover story, the work will need eggs donated by women for research, a controversial topic being considered by BRF ethicists.

Human egg research must be privately funded.  Due to the National Institutes of Health budget no federal dollars can be used to study activated human eggs, or parthenote stem cells.  Bedford Research is uniquely positioned to push this field forward, and needs to add two additional scientists in 2016 to optimize progress. Progress depends entirely on private donations.

Check out more news in the BRF Fall 2015 Newsletter.

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Meet our new board members!

The Bedford Research Foundation welcomes two new board members to the Board of Trustees:  Larry LaFranchi, Ellen Sheehy and Scott Anderson.

Larry LaFranchi brings more than 30 years of business and entrepreneurial experience. His passion for health care and is a perfect match for the Foundation’s independent research goals, and his expertise in financial planning and consulting will benefit all aspects of research planning.

Ellen Sheehy is an experienced, analytical entrepreneur with broad experience in strategy development and implementation.  She has been a leader in the field of nonprofit healthcare for many years.

Scott Anderson is an experienced computer developer and technical science writer. He co-authored Human Embryonic Stem Cells with Dr. Kiessling.

Check out more news from the BRF Fall 2015 Newsletter.

Research Update: induced pluripotent stem cells

This past year BRF helped sponsor a research fellow, Sebastian Bernabe, in Andulacia, Spain’s new stem cell research center.  Formerly a research fellow with Foundation Trustee Dr. Jose Cibelli at Michigan State University, Dr. Bernabe joined the spinal cord research team developed with Spanish scientists Dr. Cibelli and Dr. Philip Horner.  The goal of the research was to test the safety of another innovative stem cell, “induced pluripotent stem cells,” orpasted-image IPS cells. These cells are derived from skin biopsies and were used to treat spinal cord injury in a rat model system.

The  transplant was performed Oct 28, 2015 after several years of research. It will take months before results are known.

 

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Innovative Stem Cells for EVERY Body

Bedford Research scientists are launching research to derive new stem cells from unfertilized human eggs.  These cells, termed “parthenote” stem cells, are being developed to fulfill the need for “off the shelf” stem cell treatments, similar to emergency transfusion with blood bank blood.

The past decade of discoveries by BRF scientists provide the ground work for the new research initiative. Parthenote stem cells have the potential to develop into all the types of cells needed for therapies:  neurons, heart muscle, insulin-producing cells, bone marrow and cartilage cells.

New, exciting gene editing technologies have been successfully used by BRF scientists to remove the HIV-receptor (the protein on the cell surface the virus uses to infect the cell) in mouse eggs as a model system.  These recent results pave the way to continue the work in human eggs to create parthenote stem cells resistant to infection by HIV, offering the possibility of a cure  for HIV/AIDS.  The proof of principle of this approach was reported several years ago when an HIV-infected man was cured following a bone marrow transplant with stem cells from a person naturally missing the receptor for HIV.

The same gene editing technology can also be used to decrease stem cell rejection after transplantation, for example, at the site of a spinal cord injury to help prevent permanent paralysis.  Stem cells that could be universally accepted for “off the shelf” treatments of acute spinal cord injury or heart attack are exciting possibilities.

BRF scientists believe that a bank of stem cells will not only be valuable treatments for acute injuries, but also for chronic conditions, such as diabetes, Parkinson’s Disease, Alzheimer’s Disease and chronic spinal cord injury.  Such stem cell lines are also proving to be valuable models for understanding the development of cancers, such as prostate cancer and leukemia.

Read more in the fall 2015 Newsletter!

BRF Wraps Up Community Consulting Teams (CCT) Project

For the past several months Bedford Research Foundation has been working with Community Consulting Teams (www.cctboston.org) to complete a Strategic Assessment designed to help the foundation strengthen and improve communications surrounding both short and long term research projects. As part of this process, CCT has assisted the BRF in studying the potential future impacts of the work the foundation is doing. On June 9th, BRF and its team of 15 CCT MBA’s will join other organizations CCT has been working with this session to wrap up the BRF project and present findings.

Foundation Director Dr. Ann Kiessling and BRF staff are very grateful for the help and support of this wonderful organization. Below is an excerpt from CCT’s most recent newsletter:

Cutting-Edge Research to Cure Disease (BRF)
CCT is using the varied skills and backgrounds of its consultants to provide a situational assessment of the Bedford Research Foundation (BRF) to inform its strategic plan and future growth. The team is focused on understanding BRF’s mission, history, and current operations by speaking with stakeholders including staff, board members, and funders. In addition, the team is analyzing BRF financials, identifying analogous organizations to determine successful models for growth, and researching potential funding sources.

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