Special delivery: Discovery of viral receptor bodes better gene therapy

There is much hope for gene therapy’s future potential to treat a number of human diseases. The use of adeno-associated virus (AAV) vectors to transport genetic material into cells has been critical to the initial success of experimental gene therapy treatments of hereditary diseases, including hemophilia B.  But in order to develop gene therapy cures for additional diseases and conditions, like diabetes and heart disease, it will be necessary to deliver the treatment to specific tissues. Achieving this required an understanding of how AAV enters cells. 


Michael Chapman, Ph.D.

Now, for the first time, researchers at OHSU and Stanford have identified the protein (KIAA0319L) to which AAV adheres on the outside of human cells and uses to gain entry, a discovery published in the journal Nature

The paper, “An essential receptor for adeno-associated virus infection,” is jointly authored by Michael Chapman, Ph.D., R.T. Jones Professor of Structural Biology, OHSU School of Medicine, and Jan Carette, Ph.D., Assistant Professor, Microbiology & Immunology, Stanford University School of MedicineMajor contributors to the study include Sirika Pillay, Ph.D., Stanford University School of Medicine, and Nancy Meyer, M.S., Research Associate, OHSU.  

The following post about the study originally appeared on Stanford Medicine’s blog, Scope.

Special delivery: Discovery of viral receptor bodes better gene therapy
Written by Bruce Goldman
Photo by Loco Steve

Photo by Loco Steve

Gene therapy, whereby a patient’s disorder is treated by inserting a new gene, replacing a defective one, or disabling a harmful one, suffered a setback in 1999, when Jesse Gelsinger, an 18-year-old with a genetic liver disease, died from immense inflammatory complications four days after receiving gene therapy for his condition during a clinical trial. It was quite a while before clinical trials in gene therapy resumed.

But what Stanford virologist Jan Carette, PhD, describes as “intense interest” in the field is once again in full bloom. Gene therapies for several inherited genetic disorders have been approved in Europe, and a gene-therapy approach for countering congenital blindness is close to approval in the United States.

That a virologist would be paying such close attention to this topic isn’t odd, as the most well-worked-out method for introducing genetic material to human cells involves the use of a domesticated virus.

If there’s one thing viruses are really good at, it’s infecting cells. Another viral trick is transferring their genes into cellular DNA — it’s part of their modus operandi: hijacking cells’ replicative machinery and diverting it to production of numerous copies of themselves. Scientists have become increasingly adept at taming viruses, tweaking them so they retain their ability to infect cells and insert genes, but no longer contain factors that wreck tissues or taunt the infected victim’s immune system into a rage destructive to virus and victim alike.

Adenovirus-associated virus — ubiquitous in people and not associated with any disease – makes a great workhorse. Properly bioengineered, it can infect all kinds of cells without replicating itself inside of them or triggering much of an immune response, instead obediently depositing medically relevant genes into the infected cells to repair a patient’s defective metabolic, enzymatic, or synthetic pathways.

Figuring out how to tailor this viral servant so it will invade cells more efficiently, or invade some kinds of cells and tissues but not others, would broaden gene therapy’s utility and appeal. In a series of experiments described in a study in Nature, Carette’s group, with collaborators from Oregon Health & Science University and the Netherlands, used a sophisticated method pioneered by Carette to bring that capability a step closer.

A virus can attach itself to a target cell by latching onto a molecule embedded in that cell’s surface. In the case of adenovirus-associated virus, that viral-receptor molecule is already known. (The molecule obviously is there for some constructive purpose, which doesn’t stop the invading virus from taking advantage of the mutual attraction.) Simply glomming on to the cell’s surface isn’t enough, though. To get to the all-important nucleus, where the genetic jewelry is ensconced, the virus has to penetrate the cell as well. Until now, the molecule on which adenovirus-associated virus hops a ride downtown was anybody’s guess.

In the new study, Carette and his colleagues identified, in human cells, precisely that transport molecule. This discovery could lead to ways of raising or lowering the molecule’s expression in different tissues so that therapeutic genes get delivered to their intended addresses, and nowhere else.


Read more:
Portland Business Journal: OHSU researchers reach major gene therapy breakthrough
MedCity News: Researchers in Oregon are changing the face of gene therapy with new breakthrough

Neurosurgery resident waltzes through joys of ballroom dance

There may be a joke out there somewhere about how ballroom dancing is hardly brain surgery, but Kunal Gupta isn’t likely going to be the person to make it. Instead, Gupta, a native of the United Kingdom, is actually someone with an affinity for and a connection to both brain surgery and ballroom dancing.

Now in his fourth of seven years as a neurosurgery resident at Oregon Health & Science University, Gupta, MBChB, PhD, grew up in Birmingham, England, where he took a fair amount of acting classes. To complement those, his parents also enrolled him in a few dance classes at a local recreation center.

Though he never fully dove into the pastime as a youngster, the exposure to dance did leave an impression.ballroom-02

“It was just one of those experiences that kind of stuck with me,” said Gupta, now 32. In fact, it stuck with him so much that when he arrived at the University of Cambridge for medical school, Gupta decided to try out for the Cambridge University Dancesport Team.

The team represents the university at national competitions across the country, competing in five ballroom dances — waltz, quickstep, foxtrot, Viennese waltz and tango — and five Latin American dances, including jive, samba, rumba, paso doble and cha cha.

Gupta didn’t make the first team on his first try, but a year later he did, which set the stage for his enjoyment of competitive ballroom dancing to take off.

“It’s not so much fun when you’re a 12-year-old kid,” Gupta said, “but it gets much more interesting when you’re an adult.” As part of the team at Cambridge, Gupta built up his dancing deftness and moved his way up in the ranks.

While studying for a time in Edinburgh, Gupta wanted to keep his dancing sharp and needed to find a partner. He found one in a young researcher and dancer who also happened to be studying in Edinburgh just two labs away from Gupta.

The two began dancing together and, eventually, they married. “It’s funny, but it’s how I met my wife,” Gupta said.

In addition to his wife, Gupta danced with many different partners while he competed at Cambridge and in a few amateur competitions. He described the competitions as “these amazing round robins” where 20 different couples all dance and are judged at the same time.

“You spend half the time trying to dance and half the time trying not to trip over or run into everyone else around you,” he said. “It’s really fun.” Gupta also said he enjoys the music that accompanies ballroom dancing — plenty of big band music from the 1920s and 1930s — and the social interaction that dancers share.

In addition, he said that at Cambridge, many of the dancers were in fields more closely related to science than, say, the humanities, so there has been that connection for him as well.

“There are a lot of technical steps involved to do it right, so I think that is very appealing,” Gupta said. When he was competing, Gupta and his partners did fairly well, winning some competitions or at least making a solid showing.

At the more advanced level, however, Gupta said it’s hard to compete against people who have been dancing seriously since they were children. “You can’t compete with that,” he said, “but it’s an honor to be dancing beside people who are that good.”

ballroom-01Though Gupta and his wife, E. Jolanda Muenzel, MD, PhD, a post-doctoral fellow in neuroscience at OHSU, still dance occasionally, they have found that their time is monopolized these days by work and study.

Gupta, who has a bachelor of medicine and a bachelor of surgery and also a PhD from Cambridge, is at a point in his residency where he is taking care of critical patients and assisting surgeons.

He is also gaining more autonomy in the operating room as he works toward ever more complex surgical procedures.

While his earlier research focused, according to an OHSU bio, on “the novel discoveries he made around glial-neuronal interaction under molecular paradigms of traumatic brain injury, using a human stem cell platform,” Gupta’s main interest these days is in epilepsy, as it is an affliction where a strong case for surgical treatment, rather than pharmaceutical treatment, can be made.

He said he plans to use his sixth year of residency for epilepsy research, followed by his seventh and final year of surgery.

After that, Gupta, who also enjoys tennis, skiing and snowboarding, is hopeful that eventually his schedule may free up time for a little more dancing. “I’d love to because it really is a lot of fun,” he said. “Maybe when I have more control over my schedule.”


This article was originally published in The Scribe, a publication from the Medical Society of Metropolitan Portland.

Your health questions answered: Is pain a part of Parkinson’s disease?

You ask. OHSU experts answer.

Q: I was once told that pain is not a part of Parkinson’s disease. Is that true?

A: Pain is a common symptom in people with Parkinson’s Disease (PD) and people with PD are more likely to have pain than those without PD.

86810406It is unclear what causes this increase of painful symptoms, however.

There are several theories including loss of dopamine or other neurotransmitters (natural chemicals) in the brain, alterations of nerves in the skin, or the general muscle stiffness and reduced movement caused by PD.

Pain in PD is commonly divided into five categories:

• musculoskeletal (inflammation of muscles, tendons, ligaments and bones as in arthritis)

• dystonic (an abnormal pulling or twisting of muscles)

• central (related to changes in the brain)

• akathitic (a restless or uncomfortable feeling)

• radicular/neuropathic (caused by damage to nerves in the back or limbs)

Due to the lack of understanding of the mechanisms of pain in PD there are no guidelines for the optimal way to treat it; however, there are many treatments that can be considered including physical therapy, optimizing PD medications, and using analgesics (medications that treat pain).

Treatment is individualized based on the type and location of the pain. If you suffer from pain, please talk to your neurologist about how they can help.




Keiran Tuck, M.B.B.S.
Fellow, OHSU Parkinson Center

Study hopes to clarify the link between sleep problems and Alzheimer’s disease

An upcoming study led by Jeffrey Iliff, Ph.D. and Bill Rooney, Ph.D. hopes to clearly determine the relationship between a lack of sleep and Alzheimer’s disease. The team received funding from the Paul G. Allen Foundation to test their approach. They hope to begin scanning the brains of participants within a year, using a 7-Tesla MRI (pictured below).

Iliff and Rooney recently spoke to Jon Hamilton at NPR’s Morning Edition about the upcoming study and the importance of adequate sleep.

Listen to the full NPR interview here.

MRI Photos_7

MRI Photos_24

Jeffrey Illiff and Bill Rooney with the 7-Tesla MRI.

Jeffrey Illiff and Bill Rooney with the 7-Tesla MRI.

Year in review: The most popular “On the Brain” posts of 2015

As we welcome in the new year, here’s a look back at the brain-related news you may have missed; a round-up of our most read blog posts of 2015:

1. Acupuncture and diet changes to treat neuropathic pain

Peripheral Neuropathy is a common neurologic condition, which affects the peripheral nerves. The most common symptoms associated with peripheral neuropathy are burning, tingling pain, which often feels like sharp electric sensation. More…painful_feet_L-286x300

2. Dietary and lifestyle modifications for migraine prevention

Years ago, my headache mentor at Columbia, Dr. Green, compared a migraineur’s brain to a fancy sports car’s engine.

He meant that the brain becomes sensitized to the slightest stimulation and like the engine of a fine sports car, it revs up with the slightest stimulation. More…

3.  Five things you should know when caring for a loved one with dementia

Caregiving for a loved one with dementia can be challenging to your family dynamics, your finances, and more. 

But did you know, it can also be hard on your emotional and physical health? More…

4. Healthy aging and preserving community memories

swimming dive copyThe Layton Aging and Alzheimer’s Disease Center in partnership with the Center for Healthy Communities is launching a first-of-its kind study around brain health intervention.

The innovative program aims to boost cognitive health within the African-American community in Portland. More…

5. Sleep expert shares his secrets for easing into the upcoming time change

The end of daylight saving time is soon approaching, and while most of us look forward to that “extra” hour of sleep, there are a few things to think about when society’s clock changes, but our biological clock doesn’t. More…

6. Early diagnosis of Alzheimer’s disease is key goal for OHSU researchers

Alzheimer’s disease is the most common form of dementia and is the sixth leading cause of death in the United States. Symptoms include memory loss, personality changes and trouble thinking, and the disease typically worsens over time. More…

7. Research affirms use of thrombectomy procedure for stroke treatment

Stroke is the fifth leading cause of death in America and a leading cause of adult disability, according to the National Stroke Association. For patients who experience strokes and the physicians who treat them, time is brain. More…

8. Researcher seeks better ways to care for people post-concussion

The research surrounding concussions has been a heavy topic of discussion and strides are being taken to incorporate research findings into clinical and practical care of people post-concussion. More…

9. The White House BRAIN Initiative in Oregon

Just over two years ago, President Obama made a dedication to support and enhance neuroscience research through the Brain Research through Advancing Innovative Neurotechnologies, or BRAIN, Initiative.

The ultimate goal, a comprehensive map of the human brain under normal conditions and in various disease states, is a daunting and perhaps unattainable task. More…backstrokes-group

10.  Stroke survivors continue to heal through the power of music

Back in early 2013, we heard about a group of stroke survivors who found their voice and some healing through music in a group known as The Backstrokes.

We’re pleased to report that the music group continues to play together. More…

Miss Oregon an important voice for traumatic brain injury

ali-wWhen I was a freshman in high school, I suffered a traumatic brain injury due to a cheerleading accident.

As someone who had no prior knowledge of brain injuries, it was difficult to understand what I was going through and why I felt so different during my recovery process.

Because of the adversities I overcame as a result of my traumatic brain injury, I wanted to advocate for this serious and often ignored issue.

After meeting with doctors and learning more about traumatic brain injuries, I got involved in volunteering and talking to students about my experiences and recovery process through OHSU’s ThinkFirstOregon program.

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Miss Oregon 2015, volunteering for a Doernbecher Children’s Hospital fundraiser

It was important to me to shed light on an overlooked issue that has not only affected me but so many others.

At the Miss America 2016 competition, I had the opportunity to represent the traumatic brain injury community with a national spotlight.

While at Miss America, I was overwhelmed with the support I received from the TBI community reaching out to me and being thankful for the attention I was able to bring to the issue.

With the constant messages, letters and phone calls from so many who were excited to hear that traumatic brain injuries were finally able to get their due, I realized one voice can really make a difference.

Ali Wallace
Miss Oregon 2015 


Donate to the OHSU Brain Institute
With your support, our scientists can decode the genetic mysteries of neurological disease and create a new standard of care for patients affected by autism, ADHD and other neurodevelopmental disorders.

Learn more at onwardohsu.org/neuro.

Neurology residents teach Milwaukie 5th graders about the brain

Alison Christy, Ittai Bushlin, and Madeline Nguyen at Linwood Elementary in Milwaukie.

Alison Christy, Ittai Bushlin, and Madeline Nguyen in a 5th grade classroom at Linwood Elementary in Milwaukie, OR.

“What have you learned about the brain so far today?”

Hands shot into the air all around the 5th grade classroom at Linwood Elementary.

“I learned that you have to wear a helmet.”

“I knew this already, but that the right side of the brain controls the left side of the body.”

It was an unusual day. As a resident in pediatric neurology, I usually spend my days seeing patients in the hospital or in the clinic, talking about seizures and headaches, medications and MRIs.

That Tuesday, I found myself instead at Linwood Elementary, with neurology resident Madeline Nguyen, M.D.; pediatric neurology resident Ittai Bushlin, M.D., Ph.D.; and Mark Rutledge-Gorman, Ph.D., a researcher who works with the Portland Alcohol Research Center and is active in outreach to local schools.

We were having a blast.

“What kinds of things can a baby do?”

“Eat!” “Cry!” “Sleep!”

“Right, a baby’s brain only has to do a few things. But it’s learning and growing all the time. What can you do? What can your brain do?”

“Learn!” “Play sports!” “Read and write!”

“What about your teacher? What does her brain have to do?”

“She has to teach us!” “She has to make us stop talking!” “She has responsibilities!”

A few weeks before that day, Madeline, Ittai and I met with Mark to plan our time with the kids. Mark has been teaching kids about science, the brain, and the dangers of addiction for fifteen years. He has Powerpoint slides and a big plastic bin with modeling clay, brain coloring pages (for making brain hats) and other activities.

The aim, he said, was to teach them that their brains are still developing, and that they can influence how it develops. There are other aims too, like learning decision-making, or developing empathy.

If your little sister is annoying, maybe that’s just because her brain is less developed than yours. If your teacher is telling you to sit in your seat, maybe that’s because her brain is more developed than yours, and because she is responsible for your safety and your education.

While Ittai squished and rolled clay brains with half the class, I gathered the other half around a blue bucket.

"Have you ever touched a brain?"

“Have you ever touched a brain?”

“What will happen if you drop this egg into the bucket?”

“I know! I know! It will break.”

“Is that our hypothesis? What’s a hypothesis?”

“It’s a test!” “No, it’s a question!”

A brown-haired girl dropped the egg. It cracked, but didn’t break. Hypothesis tested.

“Let’s come up with another hypothesis. What will happen if I wrap this egg in newspaper and bubble wrap and put it in this box, then drop it into the bucket?”

The same girl dropped the wrapped egg. No cracks!

“Now let’s talk about helmets. How does a helmet protect your brain?”

Why did we all choose to spend that rainy Tuesday afternoon at Linwood Elementary?

First of all, we were there to help the kids learn about ways to protect their brains, by wearing helmets and avoiding alcohol and drugs.

There isn’t always enough time in a doctor’s appointment to explain not only what a child should do to be healthy, but why it’s necessary.

Hopefully, some of those children will think twice before getting on a bicycle without a helmet, or taking a first sip of alcohol.

Mark, Madeline, Ittai and I are also people who love science and the incredible things the brain can do, and we hope that our love might be infectious.

It never occurred to me that I could get a Ph.D. until I met professors when I was in high school. I didn’t think about getting a medical degree until I met doctors who did science and realized that those things could work together.

Maybe some of the kids in this class will see these doctors and scientists who are clearly very excited about brains, and start thinking that they, too, could study medicine or science.

And there’s another ulterior motive.

“Does anyone have any last questions?”

A boy stood up, his hand raised high.

“Have you ever touched a brain?”

I have. It was pretty cool. Sometimes I forget that what I get to do, every day, is amazing. There is nothing like the enthusiasm of a 5th grader to remind me that I am so lucky to have this awesome job.

I hope he gets to touch a brain someday.


Alison Christy, M.D., Ph.D.
Pediatric neurology resident
Oregon Health & Science University


Donate to the OHSU Brain Institute
With your support, our scientists can decode the genetic mysteries of neurological disease and create a new standard of care for patients affected by autism, ADHD and other neurodevelopmental disorders.

Learn more at onwardohsu.org/neuro.


Valerie Palmer recognized for innovative social-impact contributions

Valerie Palmer, faculty instructor at OHSU, was recently selected by Encore.org as one of 41 Purpose Prize Fellows for her work creating an education exchange, bringing services to immigrant refugees and raising health-care professionals’ cultural awareness and cooperation.

Encore.org is a national nonprofit that is building a movement to tap the experience of people in midlife and beyond who are using their encore years – the time of traditional retirement – to undertake powerful social-impact projects.

Valerie S. Palmer

Faculty Instructor, Oregon Health & Science University (OHSU) and Board President, Immigrant Refugee and Community Organization, Oregon Health & Science University, Global Health Center
Purpose Prize Fellow 2015

Struggle to understand and prevent brain diseases in children;  a global problem

The struggle to understand and prevent brain diseases in children; a global problem

I was born in South Africa under apartheid. As a person of mixed race, my skin color led to discrimination, in society and within my family. As the oldest girl, I looked after my siblings, cleaned house, prepared meals, cared for farm animals and walked miles to school each day. And when I was sick, I had compassionate medical care from a beloved local physician, whose respect for life stood in sharp contrast to the apartheid regime.

At 17, I left South Africa, eventually finding sanctuary in the United States, where I acquired freedom, education and full enfranchisement previously denied.

My early research stimulated me to create a nonprofit focused on health disorders in low-income countries. Later, in the field and laboratory, I explored neurological disorders across the world. In 2007, when the OHSU Global Health Center opened, I began to share my knowledge with students entering the health professions….

Continue reading Valerie’s story at Encore.org

Learn more:
Conference paper on research conducted in Gulu, Uganda
Inter-professional Community Health & Education Exchange (iCHEE)
The Oregonian: “OHSU program gives immigrants, the unemployed and underemployed a way to get health checkups”


Donate to the OHSU Brain Institute
With your support, our scientists can decode the genetic mysteries of neurological disease and create a new standard of care for patients affected by autism, ADHD and other neurodevelopmental disorders.

Learn more at onwardohsu.org/neuro.


Give Time: 3 ways to increase face-to-face contact with loved ones

With Thanksgiving just behind us and the end-of-the-year holiday seasons fast upon us, our minds often turn to our loved ones.

In my family, we have made a conscious effort (and yes, with airfares these days, not a cheap one either!) to gather with an assortment of family members around Thanksgiving and Christmas.

Though it can be an effort to meet up with family and friends, recent research brings home the point that this extgive-time-neuroFBra effort likely translates into significant benefits for our mental well-being.

In a study I led examining data from over 11,000 adults over age 50, we found that those regularly spending face-to-face time with friends and family had significantly reduced risk of developing clinically significant symptoms of depression years later.

Other modes of having social contact—calls on smart phones, emails and letters—were not robustly associated with depression.

Here I offer a few practical tips to keep in mind as you prepare for the holidays.

Schedule face-to-face visits with friends and family into your monthly calendar.

The more often you spend time face-to-face the better, but our data showed that even those who got together once or twice a month had significantly lower rates of depressive symptoms. Just like other important activities in your life, make sure you schedule it in!

Don’t get together if it’s going to stress you out.

Social relationships contribute to our happiness and healthiness, but they actually do more damage if the relationship is toxic. Face time should be fun time, not argument time.

For those with loved ones far away, try to develop local support networks for them.

Let’s face it: if your parents live 3,000 miles away, it is not realistic to get together every week with them. However, if you can see to it that they join a club or social group (pick one based on their hobbies or interests), they can get together weekly and offer similar mental health benefits.

Detailed results from our study are published in the Journal of the American Geriatrics Society.




Alan R. Teo, M.D., M.S, Assistant Professor of Psychiatry at OHSU and Core Investigator, VA Portland Health Care System.





Donate to the OHSU Brain Institute
With your support, our scientists can decode the genetic mysteries of neurological disease and create a new standard of care for patients affected by autism, ADHD and other neurodevelopmental disorders.

Learn more at onwardohsu.org/neuro.

Cleaning while we sleep: A novel approach in Alzheimer’s research

ThinkstockPhotos-490755478Every 67 seconds, an American develops Alzheimer’s disease. It affects 5.3 million people in the US and if no medical breakthroughs to prevent or cure the disease are found, this number will triple by 2050.

In 2013, Jeffrey Iliff helped discover how our brains flush out toxic waste as we sleep. This is waste that builds up in our brains during the day – including the Alzheimer’s-linked protein, amyloid beta.

His findings, which he’s advancing by the day, could potentially lead to the treatment, and maybe even prevention, of Alzheimer’s. We catch up with him to find out about how his work has developed over the past few years, the unforeseen twists and turns that led him down this important avenue, and what he looks for in the next generation of Alzheimer’s researchers.

Why are our sleeping brains pertinent to our brain cleansing system?

It seems that sleep has evolved to maximize a bunch of maintenance-type functions in our brain, and this cleaning process one is just one of them. It’s arguably not even the most important one. But for whatever reason, our brain function is optimized when these housekeeping functions happen during sleep, allowing us to maximize our performance while we’re awake.

But why that is we don’t really know yet.

You helped discover an important potential link between sleep and the development of Alzheimer’s disease. What were your key findings?

There are two main findings in our research that everything else rests on. The first is in a paper we published in 2012 about cerebrospinal fluid circulation. This is the fluid that surrounds the brain. We were able to show that a substantial portion of it is actually recirculating back into and through the brain.

It does this by essentially using the blood vessels as a scaffold to provide access to the entire brain tissue. The movement of this fluid along vessels and through the spaces between the brain’s cells appears to be involved in the clearance of amyloid beta out of the brain interstitial fluid.

The second main finding relates to a paper we published in 2013. Here, we showed that this cleaning process is primarily a feature of the sleeping brain. Both the movement of cerebrospinal fluid along the outside of blood vessels and back through the brain, and the clearance of amyloid beta, occur much more rapidly in a naturally sleeping and anesthetized brain, compared to the waking brain.

How has your research developed since this finding? What new information have you brought to light?

To boil it down, our current research focus is essentially to analyze what’s going wrong within this cleaning system at a molecular level, and then to translate that into human subjects.

Firstly, our last few papers have shown that in both the aging and injured mouse brain, this cleaning of the brain slows down. We want to define on a molecular and cellular level what’s going wrong in the aging and injured brain that’s slowing down this process, and whether that makes it vulnerable to amyloid beta deposition or tau aggregation.

But at this point, none of this work has been validated in humans – we don’t really know if this cleaning process happens in the human brain during sleep, much less whether this process contributes to the development of Alzheimer’s in people.

So I’m excited that we’ve received funding from the Paul G. Allen Family Foundation to look into this. They are funding our group to extend our work on sleep and the aging brain – essentially from mouse models into humans.

The first step in that process is to develop clinical imaging approaches to measure the system’s activity in the sleeping and waking human brain. The study will then move on to analyze that process in the aged human brain, and in the brains of people who appear to have the beginnings of Alzheimer’s disease.iliff-ted

How might your research and recent developments help prevent Alzheimer’s disease?

The encouraging thing is that there’s an increasing push on the therapeutics’ side to identify people who don’t have Alzheimer’s disease yet, but are expected to at some point in the future. That’s one of the motivations behind the development of amyloid PET imaging and cerebrospinal fluid biomarkers, for example.

A study that just came out of Washington University in St. Louis reported that CSF biomarkers consistent with Alzheimer’s disease could be detected as early as 45 to 55 years of age. If amyloid deposition begins that early, then it’s possible the failure of this clearance system is happening even earlier.

So, if we can develop imaging approaches that aren’t prohibitively invasive, then it may be possible to identify people who may be susceptible to amyloid beta deposition in the decades to come. That would offer a very wide window for lifestyle interventions, or drug therapies if effective drugs can be developed.

That’s the really exciting and promising thing for the future: First, this cleaning system may be a new therapeutic target, and imaging it may allow us to develop a new biomarker that identifies vulnerability at an earlier stage in the disease process than our current biomarkers can.

How long do you think it will take to reach this point?

A number of important things still need to be done. I think we’ll know whether these ideas have legs and traction in the next three to five years. If the function of this system can be validated in human subjects, and if its impairment can be causally linked to amyloid beta deposition, then things move on to identifying drugs that might modulate this pathway. That can go quickly or slowly depending on what the data looks like.

Has your research taken any unexpected turns?

The magnitude of the sleep-wake effect was very surprising. But admittedly, all of this research has been one big, unexpected turn that we’ve been trying to chase and learn from along the way.

My background isn’t in Alzheimer’s disease or sleep at all – it’s in vascular physiology. I started my postdoc in a glial cell biology lab and thought I’d be a basic science researcher for the duration of my career. The shift to clinical subjects and clinical samples wasn’t something I anticipated, but it’s probably been the most exciting thing that’s happened in my career.

What event sparked the change in your career?

Jeffrey Iliff, Ph.D.

Jeffrey Iliff, Ph.D.

For my PhD, I studied the regulation of brain blood vessels, which is really a largely vascular subject. At the beginning of my post doc I went to talk to my supervisor, Maiken Nedergaard, and she showed me a paper written in 1984. It was by the American neuroscientist Patricia Grady about the movement of cerebrospinal fluid tracers into the brain along blood vessels, and was a somewhat controversial paper at the time.

I was only five years old when the study came out, so when Maiken said, “I want you to redefine water movement in the brain,” I had almost no idea what that meant at all! It was a whole field that at the time I knew nothing about, and she knew very little about.

So, almost from day one it was like we were wandering out into the middle of nowhere, and then we happened to hit this major road – a road that has been very, very interesting. And we’ve been working on it together, and then separately in our own labs, ever since.

What was your greatest ‘eureka’ moment in the lab?

The biggest eureka moment for me was when I was doing the dynamic imaging of the vasculature in the brain. I now use these videos in every talk that I give because they are so evocative. It’s like this: the blood vessels are always red and the tracer we inject into the cerebrospinal fluid circulation is always green.

You see the red blood vessels there, and then the green tracer runs into the screen along the outsides of the vessels – it forms a halo around the blood vessel as it moves through the perivascular space.

The first time I saw that it really struck me because I was expecting something very, very different. I thought the green cerebrospinal fluid would flood over the screen, for example. But instead, it was restricted to this very narrow, anatomical pathway; it was so specific in where and how it moved.

The fact I could see it happening in front of my eyes in real-time, and follow and chase it around, made it very real for me. And then the videos that come from this imaging are extremely believable and compelling for other people, too – in a way that an image of fixed tissue in a paper isn’t. So that was a big moment – one that drove me forward in my research.

You have a postdoctoral position open in your lab. Do you have any advice or tips for people thinking of applying, or for those entering your area of research?

When I’m looking for a post doc I’m not looking for a technician. I can get hands – that’s not a problem. What I want is people who have better ideas than I do; I want people in my lab who are more creative than I am, and that can bring something new that’s going to change my science.

Having a different background is extremely valuable because you can offer a new take on the science that we’ve been looking at the same way for the last 5 years.

I’m also looking for someone who has a defined idea of what they want to do when this post doc is over. Many applicants don’t have a clear vision of how they’re going to become an independent researcher – which is an end goal I hear a lot.

My goal is to help them get there, I’d love to do that. But if they haven’t thought of how their science and my science can interact in a way to get them there, then they’re missing a critical step.

In the interview I want to see this drive, energy, creativity, and familiarity with our work. And that’s because when I hire for these post doc positions, I’m looking for a potential partner.

This story was originally published on ResearchGate News to highlight the work of neuroscientist Jeffrey Iliff (Oregon Health & Science University) for this year’s World Alzheimer’s Day on September 21, 2015.

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