OHSU researchers develop a novel gene and stem cell technique for treating mitochondrial disease

Stem cell colony

Stem cell colonies growing on top of feeder cells with immunochemistry staining

A study led by OHSU researchers Shoukhrat Mitalipov, Ph.D., and Hong Ma, M.D., Ph.D., at the Center for Embryonic Cell and Gene Therapy and the Oregon National Primate Research Center, has revealed a critical first step in developing a new gene and stem cell regenerative technique for treating patients with mitochondrial disease.

Dr Hong Ma-headshotJPG (2)

Hong Ma

Mitochondrial diseases result from DNA mutations that lead to altered cell function. Cell injury and cell death result which can lead to multiple system failure and even death.  In the United States, up to 4,000 children are born with a type of mitochondrial disease each year. There are no treatments or cures.

Mitalipov’s and Ma’s findings, published July 15 in the journal Nature, offer a potential breakthrough in treating patients with the mtDNA variant of the disease. The paper, “Metabolic rescue in pluripotent cells from patients with mtDNA disease,” outlines a mitochondrial replacement method used to create a stem cell with healthy mitochondria from a patient’s skin cell containing mtDNA mutations. To conduct this study, the researchers first collected skin cells from patients with mtDNA mutations. They then recovered the nucleus from the skin cells and paired them with healthy donor cytoplasm, the material surrounding the cell’s nucleus that contains the mitochondrial DNA, from an egg. This resulted in an embryonic stem cell with healthy mitochondria.

Shoukhrat Mitalipov

Shoukhrat Mitalipov

Reinserting genetically correct cells into the patient to replace diseased tissue is more precise than traditional gene therapy, which involves inserting synthetic genes into patients via viruses. This nuclear transfer technique could pave the way for treating many diseases caused by DNA mutations.

Read more.

The study, “Metabolic rescue in pluripotent cells from patients with mtDNA disease,” was funded by the Leducq Foundation, Mayo Clinic Center for Regenerative Medicine, OHSU and University of California, San Diego institutional funds. Work in the laboratory of J.C.I.B. was supported by the G. Harold and Leila Y. Mathers Charitable Foundation and the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002).

Breaking news: U.S. House passes 21st Century Cures Act

The 21st Century Cures Act (HR 6), legislation that includes a wide range of provisions aimed at speeding medical innovation and regulatory approval, received overwhelming bipartisan support today with a vote of 344-77 in favor of passage. One hundred seventy Republicans and 174 Democrats voted in favor and 70 Republicans and 7 Democrats voted no.  Oregon’s five Members of Congress supported the legislation. The House also rejected an amendment that would have converted the NIH Innovation Fund from mandatory to discretionary funding.

The bill, if  it passes in the U.S. Senate, will provide an additional $9.3 billion in funding to the NIH and FDA and sets up frameworks to evaluate data more efficiently to better determine the safety and efficacy of new treatments. After seeking input from the medical research community, including OHSU, the House Energy and Commerce Committee incorporated additional funding for NIH at levels that represent an increase of $1.5 billion per year for three years. The bill also allows for the creation of an NIH Innovation Fund that would provide $8.75 million in funding over the next five years. The House rejected an amendment that would have converted the NIH Innovation Fund from mandatory to discretionary funding.CuresActCongress

HR 6 was introduced in an effort to improve and speed patient access to new therapies by accomplishing the following:

  • Removing barriers to increased research collaboration
  • Measuring success and identifying disease earlier through personalized medicine
  • Modernizing clinical trials
  • Removing regulatory uncertainty for the development of new medical applications
  • Providing new incentives for the development of drugs for rare diseases
  • Helping the biomedical ecosystem coordinate more efficiently to find faster cures
  • Investing in 21st century science and next generation investigators

A short summary of the bill can be found here. For additional details, read this. You can also watch Congressman Greg Walden give a shout out to OHSU for providing input and supporting this legislation.

West Nile virus vaccine developed at OHSU enters human clinical trials

Mark K. Slifka

Mark K. Slifka, Ph.D., professor and senior scientist, Division of Neuroscience, ONPRC, and Department of Molecular Microbiology and Immunology, OHSU School of Medicine

A new NIH-funded investigational vaccine to protect against West Nile Virus, discovered and developed by OHSU researchers, is entering Phase I clinical trials. The OHSU team, led by Mark Slifka, Ph.D., created the test vaccine, called HydroVax-001, with a novel hydrogen peroxide-based approach that renders the virus inactive while maintaining its integrity; an intact surface structure permits triggering of an immune response to cells infected with the virus. This preparation will allow the test vaccine to be administered to a diverse population, including those most vulnerable to the virus such as the elderly and immune-compromised individuals.

West Nile Virus first appeared in the U.S. in 1999 with 62 cases and 9 related deaths reported. It has become a significant public health concern: 41,762 cases of the disease have been confirmed in the United States since it was first reported, and 1,765 people have died from the disease. Spread through the bite of mosquitoes, West Nile Virus also infects birds and other animals. There is an effective veterinary vaccine. No human vaccine, however, has yet been approved.

In preclinical studies, the test vaccine was effective at protecting mice against a lethal dose of the virus by eliciting an immune response that killed infected cells. The clinical trial will test the safety of the vaccine and its ability to produce an immune response in humans.

The investigational vaccine was developed with funding from the National Institute of Allergy and Infectious Diseases (NIAID), and NIAID will sponsor this trial at one of its Vaccine and Treatment Evaluation Units at Duke University in North Carolina. Enrollment is expected to be completed by December 2015. holds joint appointments with the Division of Neuroscience, ONPRC Department of Molecular Microbiology & Immunology at OHSU

Who’s new at OHSU? Shawn Chavez, Ph.D.

Shawn Chavez, Ph.D., is an assistant scientist in the Division of Reproductive and Developmental Sciences at the Oregon National Primate Research Center and an assistant professor in the OHSU School of Medicine Departments of Obstetrics and Gynecology and Physiology and Pharmacology. Her paper “Prediction model for aneuploidy in early human embryo development revealed by single-cell analysis” was published online on July 7, 2015, in Nature Communications.

Chavez.2015Where were you before coming to OHSU?

I came from Stanford. Much of the work I did there was in human embryology, and my focus was on aneuploidy—the loss or gain of whole chromosomes—and how it impacts in-vitro fertilization (IVF) success. IVF has been around over 35 years and is still only 30-35% successful. One thing that’s thought to be problematic, not just with IVF, but with human fecundity in general, is why we exhibit high rates of embryonic loss following IVF as well as naturally, often even before a woman would know she’s pregnant. At least 50-80% of all embryos at the cleavage stage—that is, early cell division—will have at least one chromosome affected and will probably arrest at the 8-cell stage, making them unviable. About a million embryos are produced for IVF every year in the U.S. alone, and many of them will not result in a successful pregnancy. I want to identify those that are destined to fail before they’re implanted.

What brought you to OHSU?

There are some things we can’t do with human embryos, whether it’s procuring samples, being able to establish cell lines, or other exploratory research, so the primate center was key in my decision. I had never worked with monkeys before so coming here was a real challenge, as I had to learn about rhesus physiology. But the more I delved into the literature and the work we’re doing in the lab, the more I realized I landed in the right place. Aneuploidy rates in rhesus macaque are very similar to those in humans and female rhesus macaques have comparable reproductive physiology and cycles to human females. Also, there are strict timing intervals of mitotic divisions that indicate whether an embryo will be chromosomally normal or abnormal. These intervals may be slightly faster in the macaque but the dynamics are identical. By contrast, though much research in this area has been conducted using a mouse model, mice exhibit only around 1-10% aneuploidy. Macaques are the perfect model for my work and unlike mice, are released back to the colony following IVF.

What specific avenues of research are you exploring?

Examining cellular fragmentation more closely. Between the 1 and 2 cell stage is when you see these fragments form. They appear as small cytoplasmic balls that were thought to be empty, but we now know they can contain chromosomes. It appears fragmentation is in response to aneuploidy. What we don’t know is it trying to correct aneuploidy or trying to initiate its demise?

Rhesus embryo with fragmentation Photo by Cathy Ramsey

Rhesus embryo with fragmentation
Photo by Cathy Ramsey

DNA sequencing can now be done on a single cell level. So what we’re doing is taking 8 cell embryos and disassembling them into single cells and single fragments. In collaboration with Lucia Carbone, who investigates chromosomal rearrangements, we are DNA sequencing the whole embryo to try to reconstruct what has happened. Is there a mitotic or a meiotic error? Are there whole chromosomes or pieces missing? What is the structure of the chromosomes that remain? These are things we don’t know and are trying to find out. Being able to combine a single cell approach to answer some of the basic questions with time-lapse imaging, DNA sequencing, and gene expression allows us to correlate the data to get an idea of the full dynamic. We then hope to use these results to determine whether there are natural mechanisms such as multi-polar cell divisions or the resorption of fragments that we could exploit or other potential therapeutic interventions for improving IVF success.

We’re also looking into the male’s contribution to aneuploidy, which I think we have probably underestimated in the past.

Read more…

Workshop on reproducible research, July 22

Reproducible research provides transparency that fosters credibility and allows others to replicate findings and build on them. Recent challenges with reliability of published findings led the NIH to issue new requirements designed to enhance reproducability and various scientific journals, including Nature, have introduced new editorial methods to address the problem. But what specific measures should researchers take to meet these new standards?

Advanced software products can be used to help investigators adopt reproducibility into their research. One such tool is knitr, a package within the R statistical programming environment. Knitr uses Literate Programming to allow for results to be published alongside documentation of the steps that produced them. Curious to know how this tool can benefit your research? Attend the following workshop:ScienceCat (2)

Reproducible Research with R’s knitr package
Wednesday, July 22
2 to 3 p.m.
Vollum Institute, M1441

Presented by the OHSU Center for Health Systems Effectiveness, research associates Ben Chan, Stephanie Renfro, and Thomas Meath will review Literate Programming principles and discuss specific tools to help improve reproducibility.



TTBD Lunch & Learn: Industry-Sponsored Research, Jul. 21

If you’re interested in working with industry, this workshop can give you important insights into what you need to know for success. Panelists will discuss the life cycle of a successful industry-sponsored research agreement. Evan Lind, Ph.D., will discuss industry-sponsored research obligations from the investigator’s perspective, including how to build a successful collaboration, develop a budget, and troubleshoot. Other panelists will discuss topics such as the typical agreement negotiation process, how business development associates can help facilitate these relationships, and how to manage research that is already underway. These panelists include:

• Joseph Carroll, Business Development Director, Knight Cancer Institute
• Ruth Epling, Senior Agreements Officer, Technology Transfer & Business Development
• Pierrette Lo, Alliance Manager, Knight Cancer InstituteEvan-Lind

Tuesday, July 21, 2015
Marquam Hill Campus, Mackenzie Hall 2201
12:00pm – 1:00pm

This presentation will provide a crucial and unique opportunity to hear about industry-sponsored research from a researcher’s perspective. Post-docs, investigators, students, and those interested in the business side of science will benefit from this discussion.

This event is open to all OHSU employees, faculty and students. Admission is free, no RSVP is necessary, and complementary snacks and beverages will be provided.

Who’s new at OHSU? Sergio Fazio, M.D., Ph.D.

Meet Sergio Fazio, M.D., Ph.D., professor of medicine and director, Center for Preventive Cardiology in the Knight Cardiovascular Institute. He is board-certified in clinical lipidology, and his studies focus on the role of cholesterol in cardiovascular disease. His clinical interest is the management of patients with abnormal amounts of lipids in the blood (dyslipidemia), which includes examining lipid-lowering drugs and identifying genetic mutations causing altered lipid levels in humans. His NIH-supported research focuses on the pathogenesis of genetic dyslipidemias, early cellular events in arterial plaque formation, and gene therapy approaches to treat hardening of the arteries.

Sergio Fazio

Sergio Fazio

Let’s start with where you grew up,
I grew up in a small city called Rome. Perhaps you’ve heard of it? I never planned to leave. My family is from Rome and they are all still there. I was the first to move away.

How did you find your way to this career?
I knew I wanted to be a scientist of some kind. My first love was for geology, but I learned that if I became a geologist, I would need to leave Italy to find work and this is not what I wanted. So I settled on becoming a doctor. And then of course I ended up leaving anyway to pursue research.

What were the circumstances that led you to move to the U.S.?
I started out by earning my M.D. degree and received training as a doctor in Italy. Shortly after I completed my training, around 1985, I saw there was a revolution of molecular genetics in progress. Researchers were sequencing DNA; a brand new language was being developed. As a young doctor, I felt I wasn’t part of the conversation, but wanted to be. So I went to back to school to get my Ph.D. and that changed things. As a doctor, I never felt the need to leave Rome, but as a scientist you need to go where good researchers are clustered together and where there is money to support the research.

Read more…

2015 EURAXESS scientific communication competition now accepting submissions

The EURAXESS Science Slam North America is back! Five researchers will compete for the title of North America’s best science communicator in Chicago, Oct. 17-21. The champion will join the winners of other Science Slams held around the world for a unique networking trip to Europe in 2016.

What is a science slam? It’s a scientific talk where researchers present their work in 10 minutes or less to a non-expert audience. The presentations are judged by the audience so the focus is on teaching current science to a diverse audience in an entertaining way. This competition also gives researchers the chance to showcase their projects to their peers and the public in a relaxed atmosphere.


In North America, the competition is open to participants from all nationalities and all scientific disciplines. Candidates must be enrolled in a graduate program or working as a professor or researcher at a recognized university (or equivalent entity) in the U.S. or Canada, and be proficient in English.

To enter, candidates must complete this registration form and then either:

  • Send a video introducing or showcasing your performance. The video must not exceed three minutes in length.
  • Introduce or showcase your performance in a 3-minute Skype interview with EURAXESS Links North America representatives.

The top five submissions will receive round-trip airfare and hotel accommodations to attend the competition in Chicago this fall.

Registration open for the NIH Regional Seminar Oct. 14-16

eNIH_OER_Master_Logo_2ColorbAn NIH Regional Seminar on Program Funding and Grants Administration for 2015 will be held at the Bayfront Hilton in San Diego, CA, October 14-16. Registration is now open for this two day seminar designed for the NIH extramural community that will cover such topics as compliance, peer review, grant writing for success, pre- and post-award issues, human subject research, and electronic application preparation & submission. The event includes a session track designed for administrators as well as a redesigned track for new investigators that will focus on career mapping and the fundamentals of the funding process up to the time of award. Special interest sessions will also be held on topics such as research integrity, data sharing, training awards, and more.marina-distric-condos-san-d_720

This is a great opportunity to gain a better perspective of NIH policies and programs, network with peers, and gather helpful NIH contacts. Take a look at the agenda and register here. You can get a flavor of the presentations by checking out the seminars and presentations from the 2010 meeting, when it was held here in Portland.

CRCN meeting tomorrow, July 1: eIRB Upgrade demo

Please join the Clinical Research Coordinator Network in a special IRB presentation on the new eIRB upgrade, Wednesday, July 1. This demonstration of the new eIRB system will include a presentation of the new processes for initial submissions, modifications and CRQs, and the new Reportable New Information (RNI) system. This presentation will be followed by a Q&A session and networking.

CRCN Quarterly Meeting: eIRB Upgrade demo
Wednesday, July 1
11 a.m. to 12 p.m.

Mackenzie Hall 1168

The Clinical Research Coordinator Network fosters networking, professional development, and learning opportunities for clinical research coordinators at OHSU and associated institutions by acting as a platform for sharing information, ideas, and best practices among coordinators and other research staff.

If you have questions about this presentation or would like to get involved, please visit the CRCN Bridge Site or contact the Clinical Research Coordinator Network at askastudycoordinator@ohsu.edu.

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