New OHSU research provides key insight about mitochondrial replacement therapy

Dr. Shoukhrat Mitalipov

Dr. Shoukhrat Mitalipov

No treatments exist for children born with mitochondrial diseases, but a series of discoveries in the OHSU Center for Embryonic Cell and Gene Therapy is making progress on a technique that prevents transmission of these often-fatal genetic diseases, which are passed on from mothers to their children. The latest findings were published on Nov. 30 in the journal Nature.

OHSU scientist Shoukhrat Mitalipov, Ph.D., led a team that successfully prevented transmission of genetic defects in mitochondrial DNA in the cells of monkeys in 2009 and in human cells in 2012.

In the procedure, mitochondrial replacement therapy, the mother’s nucleus is transferred into a donor’s egg that has had its nucleus removed. The resulting egg includes the donor’s healthy mitochondria and the mother’s nucleus. This nuclear DNA determines functions ranging from organ structure and appearance to personality and intellectual characteristics.

A persistent risk with the procedure is transferring small amounts of defective mitochondria from the mother’s DNA to the donor cell, which can result in a gradual return to the mutated mitochondria and mitochondrial disease.

The findings published today suggest a way to reduce this risk — selecting egg donors whose mitochondrial DNA is compatible with the mother’s ancestral mitochondria. Similar groups of mitochondrial DNA are known as haplotypes, each of which represents major branching points on the human genetic family tree.  The team proposes setting donor mitochondrial DNA matching criteria to avoid a return of mutant mitochondria.

Mitochondrial mutations cause a range of diseases, many of which affect organs with high-energy demands such as the heart, muscle and brain. Currently, the U.S. government forbids clinical trials of mitochondrial replacement therapy. Britain has authorized such studies.  The first baby treated with mitochondrial replacement therapy was born in Mexico earlier this year.

OHSU researchers who contributed to the study also include Eunju Kang, Nuria Marti Gutierrez, and Amy Koski, members of the Center for Embryonic Cell and Gene Therapy. See the complete list of authors.

Funders of the studies include the Leducq Foundation, OHSU institutional funds and Cincinnati Children’s Hospital Research Foundation.

Read the full OHSU news release.

Funding Focus: Promoting your science, Dec. 19

In the modern information economy, it can be hard to get attention for your science—whether it’s from traditional media, social media, or even with tools like Research Gate. Join this panel discussion to learn about best practices for promoting your science and the OHSU resources that can help you. Find out how to work with OHSU’s media relations and social media departments—and what you can do to promote your research yourself.

Panelists include Tamara Hargens-Bradley, associate director, OHSU Media Relations; Kathryn Peck, social media manager, OHSU Brand Strategy; and Robin Champieux, scholarly communications librarian.

Monday, Dec. 19
noon to 1 p.m.
Vollum Institute M1441

This discussion will be followed up with an intensive workshop during OHSU Research Week, May 1-3.

Funding Focus is a series of workshops that Research Funding and Development Services offers throughout the year to share advice, tips, and general information on funding for the OHSU research community. Faculty, postdoctoral fellows, graduate students, and administrators are all welcome to attend. No registration is required.

Questions? Write

Presidential bridge funding applications due Jan. 5

The Office of the Senior Vice President for Research has released its call for proposals for the FY17 winter OHSU Presidential Bridge Funding Program. Bridge funding is available for established investigators threatened by an imminent lapse in research support. Investigators can request up to $50,000 in funding for one year to help bridge them while they generate data to restore funding. Up to 3 awards will be made this funding cycle.

Awards are available only to OHSU investigators. The PI must be an independent scientist. Independence is defined by rank at the level of assistant professor or above; committed institutional support such as space and salary; a track record of first-authored or senior-authored publications; a recent history of federal (or similar) funding; and imminently planned or pending application for funding on a national level. Postdoctoral fellows and similar trainees are not eligible to apply.

Applications must include the following:

  • Bridge Funding Request describing the need for bridge funding, efforts that have already been made to secure funding and how bridge funds will be used to increase the likelihood of funding renewal
  • Letter of support from department chair or unit head documenting, among other things, any institutional commitment to the PI during the bridging period and beyond
  • Reviewer comments and priority scores
  • CV or biosketch
  • Budget

Applications are due by 5 p.m. on Thursday, January 5, 2017 and must be submitted online via OHSU’s Competitive Application Portal (CAP). View guidelines and instructions here.

New NIH application guidelines: Changes to appendix and post-submission materials policies

NIH has released an updated application guide that includes two significant policy changes effective Jan. 25, 2017.

1) As we reported earlier this year, most appendix materials for applications have been eliminated. The only materials you may submit in the appendix section are:

For applications proposing clinical trials (unless the FOA provides other instructions for these materials):

  • Clinical trial protocols
  • Investigator’s brochure from Investigational New Drug (IND), as appropriate

For all applications:

  • Blank informed consent/assent forms
  • Blank surveys, questionnaires, data collection instruments
  • FOA-specified items. If appendix materials are required in the FOA, review criteria for that FOA will address those materials, and applications submitted without those appendix materials will be considered incomplete and will not be reviewed.

Note: Papers and manuscripts are no longer acceptable as appendix materials.  Applications submitted with other appendix materials than those listed above will be withdrawn.

2) Current NIH and AHRQ policy concerning post-submission materials has been consolidated and simplified. This applies to materials that are submitted after the grant application has been submitted but prior to peer review.  The new policy reflects the guiding principle that post-submission materials will only be accepted if they’re the result an unforeseen event. The policy does not allow for submission of materials to correct oversights or errors discovered after the application submission.

The full announcement outlines allowable post-submission materials for all applications as well as those specific to T, F, and K series applications. Detailed requirements for submitting these materials are also provided.


Upcoming OCTRI classes and presentation

Oregon Clinical & Translational Research Institute hosts classes and presentations for the OHSU research community. Next on the calendar are Epic for Research and Excel for Research.

Epic for Research
This class will cover a range of features in Epic, from identifying potential subjects to obtaining data for analysis. Panelists will discuss how Epic can support your research project.

Monday, Dec. 5
12 to 1p.m.
OHSU Hospital, 8th floor auditorium

Thursday, Feb. 23
12 to 1 p.m.
Center for Health and Healing 3181, room 1B

Speakers: Rachel Navarro from the Epic Research Team and Rob Schuff from the bioinformatics group at Oregon Clinical & Translational Research Institute

Excel for Research
This presentation will discuss best practices for managing data in Excel for research.

Thursday, Jan. 12 (Cancelled due to extreme weather conditions)
12 to 1 p.m.
Center for Health and Healing 3181, room 1B

Speaker: Julie Mitchell, Operations Manager, Oregon Clinical & Translational Research Institute

Registration is not required. Questions? Contact Kitt Swartz.

New study documents role of glial cells in brain

GCaMP6s expression

Expression of protein calcium sensors in astrocytes and traces of 10 individual astrocytes from an intact larva.

Glial cells, once considered passive bystanders of neural transmission, are now understood to provide support and protection for neurons in the central and peripheral nervous systems. Astrocytes, the most abundant glial cells in the brain, closely associate with neuronal synapses and perform supporting roles in neuronal activity by providing oxygen and sugars and by removing carbon dioxide. New research findings demonstrate a function scientists have proposed but not proven—that astrocytes not only support but actively participate in processing information in the brain.

A team of scientists led by Marc Freeman, Ph.D., director of the Vollum Institute, documented in fruit flies a newly understood pathway for transmitting signals within the brain. The research, published in the journal Nature, provided the first in vivo demonstration of astrocyte calcium signaling as essential for behaviors such as olfactory or startle responses.

The team demonstrated that neurons release neurotransmitters that bind astrocytes and change astrocyte calcium signaling, which then regulates downstream neurons. These findings make possible opportunities for the development of new, targeted therapies for regulating a wide range of neurological functions in humans, from hunger to mood.

The scientists will next investigate the extent of this type of signaling in the brain, as well as the influence of astrocytes on neuromodulators such as dopamine or serotonin.

Freeman authored the study while a professor and vice chair of the Department of Neurobiology at the University of Massachusetts Medical School and investigator in the Howard Hughes Medical Institute. Co-authors include Zhiguo Ma and Tobias Stork of the Howard Hughes Medical Institute and Dwight E. Bergles of Johns Hopkins University School of Medicine.

The work was supported NINDS grant R01 NS053538.

Read the full OHSU news release.

New research suggests travel to Mars may alter cognition

Cosmic radiation during deep space travel could alter the cognitive function and behavior of astronauts on an extended mission — such as a trip to Mars. Cosmic rays are generated in the shockwaves of exploding stars outside our solar system and are composed primarily of ionized atomic nuclei moving at nearly the speed of light. Exposure to this radiation may be unavoidable for astronauts on any future mission to Mars.

Results of a study led by Jacob Raber, Ph.D., professor of behavioral neuroscience in the OHSU School of Medicine, recently published in the journal BMC Genomics suggest that long-term exposure to cosmic radiation, particularly to Iron-56 ions, could cause symptoms ranging from memory problems to impaired judgment. Moreover, these effects could be long-lasting and perhaps without resolve.

Researchers used mice to test both short- and long-term effects of radiation. They found that exposure to Iron-56 ions significantly affects the hippocampus, which is critical for memory function. The effects of space irradiation were dose- and time-dependent, with mice receiving the lowest and highest doses of radiation exhibiting the most apparent effects, including trouble recognizing new objects in their environments two weeks later.

The research findings suggest that mice receiving the intermediate dose did not suffer memory problems because the brain responded by healing itself via epigenetic changes. The lower dose was not strong enough to trigger a meaningful response but was still damaging enough to elicit the cognitive deficit. The low dose is likely similar to the level of radiation the astronauts would be exposed to on a mission to Mars.

Better understanding the underlying mechanisms could help scientists find ways to monitor and protect astronauts from cosmic radiation in future deep-space missions and lead to the development of potential treatment options.

Research published in the paper, “Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression,” was supported by NASA grant NNJ12ZSA001N. Soren Impey assistant professor, Oregon Stem Cell Center, was the first author. Additional authors included Timothy JopsonCarl PelzAmanuel TafessuFatema FarehDamian ZuloagaTessa MarzullaLara-Kirstie RiparipBlair StewartSusanna Rosi, and Mitchell S. Turker.

Read the full OHSU news release.

Who’s new at OHSU? Vinay Prasad

Vinay Prasad, MD, MPH

Vinay Prasad, MD, MPH

Vinay Prasad, M.D., M.P.H., is a hematologist-oncologist and assistant professor in the OHSU School of Medicine. He is nationally known for his research on health policy, evidence-based medicine, bias, and medical reversal. Clinically, Dr. Prasad specializes in the care of lymphoma patients. He holds appointments in the Department of Public Health and Preventive Medicine and the Center for Health Care Ethics, where he is a Senior Scholar. We sat down with Dr. Prasad to talk about the formation of his career, his current projects, and where he sees his work going.

What’s your background?

I’m a Midwesterner from the Chicago area, and I didn’t stray far from home when I started college — I went to Michigan State University and then the University of Chicago. At MSU, I studied philosophy, writing, and science from several terrific professors, who pushed us really hard to think about our assumptions, and question them.

That was a good foundation for my experience at the University of Chicago as a medical student, which was a really special place for people who were thinking critically about medicine. I had a chance to work with physicians who cared about medical ethics, as well as those who cared about medical evidence, and all of them were superb. Finally, I completed my training at Northwestern University — where I had still more excellent role models in evidence-based medicine, and my hematology-oncology training at the National Institutes of Health, which, for me, was the ideal place to train.

When we think of medicine, we think of science, of proof. But it wasn’t until the 70s, 80s, and 90s, that we really developed a field of medicine that prioritized evidence. Before, this time though evidence was used here and there, the bulk of what you learned as a doctor was based on some very senior person telling you that’s how things were done — “This is how you recognize disease and this is what you do about it.” It comes as a shock to people outside of medicine that all medicine wasn’t always based on evidence, and, to some degree, still is not.

What knowledge do you want to see medical students graduate with?

First, you want doctors to be conscious of bedside manner. In 2016, it is of paramount importance to be good at that, and I think our training is getting much better at teaching the right skills.

Second, medical students definitely should graduate knowing how to think critically, evaluate a paper, and how to interpret statistics. The more you practice medicine, it becomes less about memorization and more about critical thinking. I also think that critical thinking is not synonymous with forced research projects. I think maybe we should move away from thinking medical students should graduate with a few research abstracts on their CV, which often rely on very unreliable methods—because that is what can get done in the time allotted. Instead, I think we have to teach the appraisal of medical evidence much more formally—much greater emphasis on study design, reliability, and how to make inferences from data. We have to teach students that medicine in the 21st century is a field where you will always be learning.

The prerequisites for medical school are tangential to medical school — calculus, physics, and organic chemistry — not to say there are no doctors that use those, but most don’t. People say those prerequisites teach you critical thinking, that they teach you memorization. But there are better ways to teach memorization and critical thinking. Philosophy is arguably something that trains you to think very critically; logic trains you to think critically; statistics too. I would consider those things. But again I would experiment, rather than mandate.

It was really in the last year of medical school and the first year of my residency that I got interested in research. I always thought I’d simply go into private practice —then, on a whim almost, I submitted a paper I had worked on — a paper that some senior person deemed “not scholarship”— to a journal. It ended up being published in the Hastings Center report. It’s fair to say that the kind of research I do — not many make a career of it. So it took me a while to realize that you can have any kind of career you want. You just keep doing it and eventually someone calls it a career.

What research are you conducting now?

Well, we have a lot of projects underway. A lot of what we’re doing is at the intersection of policy and funding and we’re doing a lot of work on is how we should pay for medical practices. If you’re in oncology, the cost of drugs is something that you cannot avoid. And we’re doing a little bit of work on in conflict of interest, prioritizing randomized-controlled trials, and some about research funding.

My goal is to try to do work that’s impactful. I aspire to do work that is read and hopefully leads people to change. For that reason I abandon a lot of projects at the outset — projects that I don’t think will be impactful, or will be published in one of the fifty thousand journals that frankly, no one reads. So, I think a lot about what I want the work to be.

Studying FDA drug approval is a big thing. Because, while there are a few drugs that are wonderful, a lot of the drugs the FDA approves are very marginal. So we’re doing a lot of work to ask should those drugs be approved, how should they be studied if they are approved, and under what circumstances should they be pulled off the market.

We have a new paper in JAMA Oncology where we start with what I think is an uncontroversial premise — that the purpose of the FDA is to approve drugs that improve survival or quality of life for people in America. That’s their purpose.

A simple fact is that the majority of drugs approved in cancer over the last 10 years are marginal. The median improvement in survival is about two months. And the clinical trials they’re conducted in are unrepresentative — they study younger and healthier patients. And, finally, when you look at how unrepresentative marginal drugs do in the real world, the answer is that they don’t do well at all — we have some evidence that shows some may not work at all.

Our conclusion is that it’s time to treat overall survival — what has always been a gold standard endpoint — in unrepresentative clinical trials as a surrogate endpoint for survival in the real world. So maybe we should actually have post-marketing commitments and grant only provision approval. Survival is, probably often, merely another surrogate. Like response rate and progression-free survival, as long as it’s conducted in unrepresented populations.

How are you finding OHSU and Portland?

I like being here at OHSU. I’ve been really impressed with my colleagues — across campus there are so many things going on. People at OHSU are working on clever projects. I think the funding for research here allows scientists to treat research as research.

I find a lot of people very like-minded on the topics I research. Pretty much, everyone I’ve met in internal medicine — and people across OHSU really. There are several senior people here who are tremendously supportive.

As for the city of Portland, I love it. I like to ride my bicycle and go on hikes. And to restaurants and the bookstore. But really? I love to binge watch television and movies. Now, Game of Thrones. And, for all time, my favorite show was the Wire.


NIH reports on R01 and R21 trends

NIH Deputy Director for Extramural Research Mike Lauer looks at funding trends and relationships for R01 and R21 mechanisms in a recent Open Mike blog post. In this follow-up to previous analyses of NIH funding competition, and outcomes for R01 “virtual A2s,”Lauer and team examined how R21s, intended to foster exploratory research at the conceptual stage, compare to R01s in terms of application and success rates and career stage of investigators applying for and receiving funding. They also investigated the relationship between the two mechanisms to see how many R21 awards were followed by similar R01 applications and awards.

Using data from 2001 onward, Lauer identified several clear trends:

Fig. 1 from  Nov. 4 Open Mike

Fig. 1 from Nov. 4 Open Mike

  • The R21 mechanism is increasingly popular but also highly competitive. NIH is seeing many more applications and awards, with growth rates far exceeding those of R01 grants. However, over time, success rates for R21 applications have been either equal to or less than R01 success rates. In FY2015, only 14% of Type 1 R21 applications were funded compared to 16% for Type 1 R01 applications.
  • More than 15% of R21 awards are followed by at least one similar R01 application but only roughly 1/3 of those applications are funded:
Fig. 3

Fig. 3

  • Most R21 applicants and awardees have previously received some NIH funding. Over the last five fiscal years, approximately 35% of R01 applications and 50% of R21 applications are submitted by new investigators. In the case of awards, 35% of R01 awards and only 34% of R21 awards are made to new investigators.

New resources to support diversity in NIH-funded research


The NIH has developed a new portal to information about how scientific workforce diversity is promoted and supported in extramural programs. The website focuses on four main areas:

Learn more and provide feedback.


Welcome to the Research News Blog

Welcome to the Research News Blog

OHSU Research News is your portal to information about all things research at Oregon Health & Science University. Visit often for updates on events, discoveries, and important funding information.

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