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Curiosity: It’s what makes new interim vice chancellor tick

Robert Eckel at desk
Dr. Robert “Bob” Eckel is serving as interim vice chancellor for research while a search for a permanent replacement is underway. Eckel has served as program director of the Clinical Translational Research Center Network of the Colorado Clinical Translational Sciences Institute (CCTSI) and the CU Adult General Clinical Research Center. He was only the second endocrinologist ever to serve as president of the American Heart Association.

It might have been what killed the cat, but to Dr. Robert “Bob” Eckel, the University of Colorado’s new interim vice chancellor for research, curiosity reigns in propelling a successful career and research program.

“It’s what drives the bus here,” said Eckel, MD, recently tapped for the job left vacant by Dr. Richard “Dick” Traystman’s death this fall, as CU administrators launch a search for a permanent vice chancellor.

Although “filling Dick’s shoes is impossible,” Eckel, an international expert in his field of lipid and lipoprotein metabolism and a recognized face on the CU Anschutz Medical Campus after nearly 40 years, said he hopes his ingrained curiosity can serve as a catalyst for furthering the research enterprise at an institution that has been good to him and his profession.

“There are many components to a successful career in science and medicine,” Eckel said. “But curiosity, in my opinion, is one of the most important factors. If curiosity is driving you, then grants, papers and quality research will follow.”

Fanning the curiosity flame

The curiosity flame was lit early in Eckel’s career. After conceding that he was no Vivaldi and ditching the thought of a profession in music (a passion that led him to his first wife, a talented violinist), Eckel decided his idea of medical school was more on track. “And I knew it would make my mother happier.”

But his vision of being solely a clinically-focused doctor soon vanished. “I found out during my residency in internal medicine that I was starting to get increasingly curious about what made people sick and why they weren’t responding to therapy,” said Eckel, an endocrinologist in both the School of Medicine’s Division of Endocrinology, Metabolism and Diabetes and Division of Cardiology. He also has an appointment in the Department of Physiology and Biophysics.

“I thought if I wanted to pursue that drive, that ultimately I needed to be trained in research,” said Eckel, crediting his subsequent research-fellowship experience at the University of Washington for fanning the flames. “I came out on fire for research.”

‘There are many components to a successful career in science and medicine. But curiosity, in my opinion, is one of the most important factors. If curiosity is driving you, then grants, papers and quality research will follow.’ – Robert Eckel, MD

Bringing a dual perspective

Eckel, who often calls himself a “cross-dresser” as a preventive cardiologist and endocrinologist, said he loves all components of his job. “As a clinician, I’m more of a preventive cardiologist, but as a scientist, I’m a metabolically-driven guy,” he said, adding that his physician-scientist perspective brings a different “twist” to the vice chancellor position.

As an investigator, Eckel thrives on being tucked in his lab, where he and Assistant Research Professor Kimberley Bruce, PhD, have expanded their longtime focus on how lipids (such as cholesterol and triglycerides) and lipoproteins (which carry lipids) relate to obesity, metabolic syndrome, diabetes and cardiovascular disease.

The two have joined forces with Wendy Macklin, PhD, a leading expert on glial biology in the Department of Cell and Developmental Biology, in investigating how lipids and lipoproteins play a role in neurological disorders, such as Multiple Sclerosis and Alzheimer’s disease, with a renewed funding award on Feb. 1.

“Myelin is loaded with lipids,” Eckel said, referring to the myelin sheath that protects the body’s nervous system. With MS, a disabling degenerative disease that affects an estimated 400,000 Americans, myelin is slowly destroyed. “So we are involved in understanding how lipids and lipoproteins can be processed to re-myelinate nerves that have been demyelinated.”

Eckel and wife at Nuggets game
Dr. Robert Eckel poses with Rocky and wife, Margaret, at a Nuggets game. Eckel credits the women in his life for much of his success.

Encouraging research partnerships

Bruce and Eckel have also teamed up with another top CU Anschutz Medical Campus researcher, SOM’s Department of Neurology’s Huntington Potter, PhD, in their work on the role of lipids and lipoproteins and the brain-degenerating Alzheimer’s disease. Alzheimer’s affects at least 5.5 million Americans, a number expected to soar with an aging population.

During her years working beside him, Bruce said Eckel has served as a great mentor and role model. “I’ve learned a great deal from Bob, not just about lipid and lipoprotein biology, but also about how to strive for scientific excellence while still keeping your feet on the ground,” she said. “I honestly can’t think of anyone better for this vice chancellor role.”

No stranger to cross-disciplinary collaboration, Eckel said researcher success also depends on networking. “None of us is an island anymore in science and medicine. There are no single-authored papers anymore. Science is really teamwork, and that’s something I will consider as I look at the big network of research on both campuses.”

Recognizing research’s influence

Eckel, winner of the Endocrine Society’s 2016 Outstanding Clinical Investigator Award, understands the power of research on both a professional and a personal level.

Diagnosed at age 5 with Type 1 diabetes, a disease he shares with two sons and opted early on to separate from his lab work, Eckel said he’s grateful for his colleagues who have made huge research strides in the insulin-related disorder.

“There’s been so much improvement in therapeutics for Type 1 diabetes,” he said. “I have a pump and a sensor,” he said, patting his lower chest, where a pump automatically infuses the insulin his body cannot make. “I’ve had this disease for 65 years now, and I’ve never felt better in my life. I feel fortunate to be alive, and that’s research,” he said.

Finding collaboration on all fronts

Eckel with family
Dr. Robert Eckel balances career and family, which includes three grandchildren and five grown children. Eckel, who emphasizes the importance of music in a well-rounded lifestyle, taught each of his kids piano until they were in sixth grade.

Eckel doesn’t just stand out in his field. In 2016, he won Father of the Year from the American Diabetes Association, for which he serves on the board. A devoted but humble family man, he doesn’t take the credit for his well-rounded success.

“It’s the women I’ve done it all with,” he said, acknowledging his first wife, who worked as a teacher while he went through medical school and then raised their five children before she died of breast cancer at age 45. “She was a great mom.”

Eckel eventually married his current wife, Margaret. “She stepped up and became a stepmom who’s now loved by all of my kids, and I’ve been married to her almost as long as I was my first wife. So I had great companionship and love from two women, and I probably didn’t deserve either one of them.”

On the professional side, Eckel said Bruce “runs the bus” in his research lab. “She’s smarter than I am. I’m lucky to have her.” With a retirement date set for July 1, 2019, Eckel hopes to have his research program ready to hand over to Bruce and to have fulfilled his new interim post to the best of his ability.

“I work at a great institution that’s been incredibly supportive, and it’s a privilege to serve,” said Eckel, who will not vie for the permanent post. “But right now, I’m neither intellectually nor emotionally ready to retire. The science is just too much fun.”

 

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CU Anschutz students present research to lawmakers at Capitol

More than 50 researchers greeted Colorado lawmakers entering the Capitol building on Jan. 19, with the aim of raising awareness of the importance of research. Colorful posters highlighting the young scientists’ projects lined the rotunda’s walls, as the presenters’ lively voices bounced around the room’s large marble structures while they explained their work.

Hannah Hathaway, PhD, is proud to share her research.

“This is such a great event,” said Hannah Hathaway, PhD, president of the University of Colorado Postdoctoral Association, as she stood amid the array of posters targeting a wide range of disciplines, from biomedical to atmospheric research. “Not only do we get to present our work in a unique way, but we also get to see other research going on in Colorado.”

Early-career scientists representing 11 state institutions of higher education, including the CU Anschutz Medical Campus, CU Denver and CU Boulder, attended the event, hosted by the CU Anschutz chapter of Project Bridge. Bruce Mandt, PhD, director of the CU Postdoctoral Office, and Jerry Johnson, the CU contract lobbyist for state relations, helped the group with the event.

Project Bridge

“The goal of Project Bridge is to give scientists more tools to succeed by teaching them to communicate outside the world of academia,” said Erin Golden, PhD, president of the national student organization. “We accomplish this through holding trainings, inviting speakers to campus and engaging in a variety of advocacy events like the Capitol Investment.”

Golden launched the CU Anschutz chapter last year after coming from Johns Hopkins University, where Project Bridge was founded.

Erin Golden, PhD, is excited with the turnout of Capitol Investment Day.

“It’s great to see everything come together,” Mandt said. “It is so important to showcase the broad range of scientific work from around the entire state of Colorado.”

Gov. Hickenlooper declared Jan. 19, 2018, “Early Career Scientist Day” to commemorate the event, aimed at showing lawmakers the importance of funding research. The event boasted 71 of 100 state legislators, who pledged their attendance as co-hosts.

Career Development

While waiting for the legislators to arrive, researchers shared their short presentations with one another. The presentations and posters were designed to be informal and jargon-free.

“This type of presentation is unusual for scientists,” Mandt said. “Our presenters are getting excellent experience in explaining their work to a lay audience. This is a wonderful career-development opportunity.”

“If I have accomplished something today, it would be relaying how impactful this scientific exploration is,” said Christopher Covey, a fifth-year graduate student in CU Anschutz School of Medicine’s Department of Immunology & Microbiology. “We’ve all worked so hard to approach scientific problems from new angles. Maybe one day we will uncover something that was previously overlooked.”

Golden hopes Project Bridge will grow to include more events and that Capitol Investment will become an annual event.

“We’re so excited with the turnout,” said Golden. “We really feel like we are making a difference in Colorado’s scientific community, while giving our peers the tools they need to succeed.”

Guest contributor: Photo at top by Katie Weeman, CIRES/CU Boulder.

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Research suggests why exercise slows Parkinson’s

Freed and Zhou
Curt Freed, MD, and Wenbo Zhou, PhD

While vigorous exercise on a treadmill has been shown to slow the progression of Parkinson’s disease in patients, the molecular reasons behind it have remained a mystery.

But now scientists at the University of Colorado Anschutz Medical Campus might have an answer.

For the first time in a progressive, age-related mouse model of Parkinson’s, researchers have shown that exercise on a running wheel can stop the accumulation of the neuronal protein alpha-synuclein in brain cells.

The work, published Friday in the journal PLOS ONE, was done by Wenbo Zhou, PhD, research associate professor of medicine, and Curt Freed, MD, professor of medicine and division head of the Division of Clinical Pharmacology and Toxicology at the CU School of Medicine.

Exercise in mice boosts protective gene

The researchers said clumps of alpha-synuclein are believed to play a central role in the brain cell death associated with Parkinson’s disease. The mice in the study, like humans, started to get Parkinson’s symptoms in mid-life.  At 12 months of age, running wheels were put in their cages.

“After three months,” Zhou said, “the running animals showed much better movement and cognitive function compared to control transgenic animals, which had locked running wheels.”

Zhou and Freed found that in the running mice, exercise increased brain and muscle expression of a key protective gene called DJ-1.  Those rare humans born with a mutation in their DJ-1 gene are guaranteed to get severe Parkinson’s at a relatively young age.

The researchers tested mice that were missing the DJ-1 gene and discovered that their ability to run had severely declined, suggesting that the DJ-1 protein is required for normal movement.

Study suggests positive human implications

“Our results indicate that exercise may slow the progression of Parkinson’s disease by turning on the protective gene DJ-1 and thereby preventing abnormal protein accumulation in brain,” Freed said.

He explained that his animal experiments had very real implications for humans.

“Our experiments show that exercise can get to the heart of the problem in Parkinson’s disease,” Freed said. “People with Parkinson’s who exercise are likely able to keep their brain cells from dying.”

Parkinson’s is a disease caused by the death of brain cells that make a critical chemical called dopamine.  Without dopamine, voluntary movement is impossible.  Most people with Parkinson’s disease take a drug called L-DOPA to treat their symptoms.  The oral drug is converted into dopamine in the brain allowing patients to get up and move.

In 1988, Freed and his colleague Robert Breeze, MD, performed the first transplant of human fetal dopamine cells into a Parkinson’s patient in the United States. His lab is currently working to convert human embryonic stem cells to dopamine neurons. These techniques should make it possible to produce unlimited quantities of dopamine cells for transplant.

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Expensive new cancer therapy may be cost effective

Researchers from the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, selected to estimate the cost-effectiveness of the newly approved CAR-T therapies, have found the clinical benefit may justify the expensive price.

The treatments involve removing immune cells known as T-cells from the patient, genetically engineering them to kill cancer cells and then putting them back in the body. The therapy is known as CAR-T or chimeric antigen receptor T-cell therapy and is FDA approved for some B-cell cancers, including acute lymphoblastic leukemia in pediatric and young adult patients and those with adult lymphoma.

Jon Campbell, PhD, associate professor of pharmacy.
Jon Campbell, PhD, associate professor of pharmacy.

The evidence suggests a potentially great benefit from these therapies, but the treatments are costly. The leukemia therapy, known as Kymriah, costs $475,000 while the lymphoma treatment, Yescarta, costs $373,000. So the non-profit Institute for Clinical and Economic Review (ICER) enlisted the help of pharmaceutical outcomes research faculty Melanie Whittington, R. Brett McQueen, and Jon Campbell from the CU Skaggs School of Pharmacy to generate evidence on whether the treatments, already approved by the FDA, are cost-effective.

The draft report of their findings was published Wednesday on the ICER website. After a public comment period, the researchers in collaboration with ICER, will finalize the report and present the findings at a public forum on March 2, 2018.

In the draft report, they compared CAR-T therapies to chemotherapy, taking into account patient survival, quality of life and health care costs from the health care system perspective over the lifetime of a patient receiving the therapies.
“We take into account the clinical evidence, quality of life data, and health system costs to generate cost-effectiveness evidence,” said Whittington, PhD, research instructor at the CU School of Pharmacy.

According to Jon Campbell, PhD, associate professor of pharmacy, the cost-effectiveness findings for both CAR-T therapies were `promising’ and suggested that they may be a good use of our health care resources toward improving health. They significantly extended the lives of some patients, much more on average, than traditional chemotherapy.

“The CAR-T science is beyond whether the therapies work for certain patients and is now questioning its value,” he said. “CAR-T is promising on the clinical side but there is some feeling of sticker shock related to the price. Is it worth it? Yes, it seems to be.”

Does the cost-effectiveness of therapies matter in the U.S.?

“The straightforward answer to that question is yes,” said McQueen, PhD, assistant professor of pharmacy. “Insurance companies have a higher likelihood of providing access and payment for therapies that are considered good value for money.”

Campbell, who is director of pharmaceutical outcomes research graduate track at the Center for Pharmaceutical Outcomes Research at CU Anschutz, noted that cost-effectiveness doesn’t mean cheapest and it doesn’t mean denying access.

“It’s about ensuring patients have access to high value care while sustaining our health system for future generations,” he said.

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CU Anschutz hosts student research forum

Why can a rhythmic tune halt the tremors and walking struggles in people with Parkinson’s disease, allowing them to dance with fluidity and box with precision? And why do some teenagers storm sobbing out of clinic doors when their providers broach the subject of weight control?

Those were two of 62 questions University of Colorado Anschutz Medical Campus students tackled as part of the 32nd Annual Student Research Forum. Posters stretched across the north and south towers of the Education 2 building, as the students presented their projects to about 400 of their instructors and peers.

“We’ve been told that the half-life of medical information is approximately seven years, so something that we are taught at the beginning of our first year of medical school may or may not be relevant at the end of our residency,” said David Nguyen, a third-year medical student, explaining the importance of the event. “Especially if we want to go into academic medicine, research is our bread and butter, and we need to stay informed.”

While learning research skills, students also benefit from networking, connecting with mentors, honing presentation skills, boosting resumes and delving into something new by taking part in research forums, said Will Dewispelaere, a second-year medical student. “We all have this inherent scientific desire to find out new things,” he said.

Will Dewispelaere
Will Dewispelaere, a volunteer presenter at the student research forum, studied the effect of rhythm on Parkinson’s patients’ brains.

Probing the Parkinson’s brain

Dewispelaere, whose undergraduate degree is in neuroscience, has had a long interest in disorders such as Parkinson’s disease (PD), a progressive neurodegenerative disease that leads to severe tremors, limb rigidity, slowness of movement and gait and balance problems.

“I’ve been involved with Parkinson’s research since my junior year in college,” he said. “For some time, we have known that if you ask some people with PD to walk, they’ll have trouble getting started. But if you ask them to snap their fingers or listen to music and then walk to the beat, they tend to have fewer problems.”

Research has linked the sound of rhythm to improvement of gait, velocity and postural stability, Dewispelaere said. “Preliminary findings showed music therapy could ease these common Parkinson’s symptoms, including depression and anxiety,” he said, noting the popularity of dancing and boxing classes for PD patients. “But no one really knew why.”

In his study, researchers compared the brains of 23 PD patients with 21 age-matched, healthy patients (HC), using a special imaging technique (magnetoencephalography). The participants tapped a button with their right fingers to rhythmic cues played in their left ears.

While both groups had similar activation in some areas of the brain, the PD group had increased activation in two right areas, one responsible for sound recognition and processing (superior temporal gyri), and the other important to the integration of sensory information, including hearing and self-motion (supramarginal).

“Our conclusion was that increased activity in these two regions of the brain allows for those with Parkinson’s disease to bypass some of their abnormal neural circuitry to generate regular movements,” Dewispelaere said.

Casillas and Vukovic
Paola Casillas and Nemanja Vukovic questioned the quality of weight-control communication between teens and health providers surrounding obesity for their project.

Closing a provider-teenager gap

Four-year medical student Paola Casillas and second-year medical student Nemanja Vukovic focused their project on improving provider and teenage patient communication regarding a top health issue of today: obesity.

“It started about six years ago with a medical student here who saw a lot of these conversations go downhill really quickly, with the teens leaving feeling very discouraged or crying or worse,” Vukovic said. “Feeling like these conversations were super counterproductive, she wanted to know what was turning these kids off,” he said.

With the help of a teenage advisory board, the students devised questions and formed focus groups, using 47 volunteers from Denver-area high schools. The most consistent finding revolved around providers’ use of the Body Mass Index (BMI) chart when initiating conversations about patients’ weight.

Most focus-group members said they disliked the tactic, Casillas said. “They said: ‘I’m not a dot on a screen. This isn’t getting to know me and finding out what I struggle with,” Casillas recounted.

Cultural and gender differences surrounding what family and peers considered appropriate weight also placed pressure on some teens. “The biggest thing we ultimately learned was that they really want the provider to get to know who they are, what their family is like, and their goals and motivations for wanting to lose weight,” Vukovic said.

The project also involved sending surveys to local providers who served teens. Nearly 70 percent of the providers reported almost always starting weight conversations with a BMI chart, with the majority also indicating that their weight-control counseling with teens was not very effective.

The good news: Both providers and teens want to see change. “I was surprised by how much they cared,” Casillas said of the high-school students. “They want to have these conversations with their providers, and they understand the importance of the issue.”

With most providers indicating interest in learning the results of the project and incorporating the findings into their practices, the student researchers aim to expand the study and develop a provider plan for tailoring weight conversations to individual patients, Vukovic said. “We found some areas of disconnect, and we are hoping to bridge those gaps.”

 

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Little understood cell helps mice see color

Researchers at the University of Colorado Anschutz Medical Campus have discovered that color vision in mice is far more complex than originally thought, opening the door to experiments that could potentially lead to new treatments for humans.
The study was published today in the journal `Neuron.’

Maureen Stabio
Maureen Stabio, PhD, assistant professor of anatomy and neurobiology

The scientists, led by Maureen Stabio, PhD, assistant professor of anatomy and neurobiology at the University of Colorado School of Medicine, discovered a new property of a little understood cell called the M5.

They knew that mice possessed light-sensitive proteins called opsins that allowed them to detect a limited range of colors. But as they investigated the role M5 cells played in this, Stabio discovered that the mice also had neurons that could compare signals from the different opsins and then send those color signals to the brain for interpretation.

“We are the first to discover this particular color vision circuit in mice,” Stabio said. “We knew they had opsins but we didn’t know they possessed the other two requirements for color vision.”

Stabio’s work focuses primarily on the cells and circuits of the retina, including a group called intrinsically photosensitive retinal ganglion cells or ipRGCs which includes the M5. These cells are primarily involved in a kind of vision known as non-image forming vision.

IpRGCs typically don’t process contrast, color, faces or art. Instead, they react to ambient light levels and send that information to the brains internal clock to put the body in synch with the rising and setting of the sun (aka the circadian rhythms).

Stabio and her colleagues found that the M5 cell, the least understood of the group, might play a role in both image and non-image forming vision.

“This adds to growing evidence that image forming and non-image forming pigments, cell types, and circuits are not as distinct as once imagined,” she said. “The two appear to be intersecting.”

But the biggest surprise was discovering that the M5 cells also process color information in mice. Mice are nocturnal and generally have poor vision. They navigate chiefly by using their nose and whiskers.

“What exactly they are doing with this color information remains to be discovered, but we know now there is a circuit for it and it’s getting to the mouse’s brain,” Stabio said.

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Graduating student finds his passion at CU Anschutz

When Andy Winter talks about the prospect of continuing his education at the University of Colorado Anschutz Medical Campus, one word comes to mind: excitement. Although he has spent the last year and a half on the CU Anschutz campus, Winter wants nothing more than to stay put.

This fall, Winter will graduate from the Graduate School with a master of science degree in Biomedical Sciences and Biotechnology.

“I knew that graduate school was in my future,” he said. “But, I wasn’t sure about jumping right into a program. So I worked in industry microbiology after finishing my undergraduate degree in biotechnology and microbiology.”

After three years in the industry, Winter missed the thrill of research. So, in 2015, he moved from Minnesota to Colorado to completely dedicate himself to applying to graduate school.

Choosing CU Anschutz

CU Anschutz was an attractive choice for Winter because of the numerous areas of research expertise on campus.

He also found the master’s program in Biomedical Sciences and Biotechnology (BSBT) at CU Anschutz especially appealing because it afforded him a flexible curriculum. He was able to navigate and sample any of the scientific disciplines CU Anschutz has to offer.

Little did Winter know that he would get much more out of CU Anschutz than just an education. It also re-introduced him to one of his passions – immunology.

Hands-on learning

Winter joined the lab of Beth Tamburini, PhD over a year ago. Although challenging, he has enjoyed his time there. While working in the lab, he conducts impactful research involving the immune system. The Tamburini lab is currently working on three different projects involving immune function. This variety of work has given him the opportunity to collaborate with other labs and extend his professional network.

“First, we are working to better understand how the immune system enhances protection against a secondary infection,” said Winter. “Secondly, we’re working with Dr. Traci Lyons to understand the role of lymphatic vessels in the immune response in breast cancer. Finally, we are working with Dr. Hugo Rosen to study lymphatic vessels and their interaction with immune cells in the liver during chronic liver disease.”

Through this hands-on laboratory work, Winter has gained invaluable knowledge and experience.

“I’m glad to be a part of this lab,” said Winter. “I’ve found immunology to be so fascinating and intricate. My understanding of immunology was limited prior to joining the Tamburini lab. The research we’re conducting is important in understanding how to better combat diseases that impact millions.”

Winter hopes to continue his professional development at CU Anschutz not only because of the campus’s cutting-edge research, but also because of its supportive attitudes.

“I’ve grown comfortable with the community of researchers and students on campus,” he said. “It has given me a strong support network and I’m dedicated to continue growing as a professional with the support of that community.”

More than academics

Despite his busy study and lab schedule, Winter found time to be an active member of the Women in STEM organization at CU Anschutz. He also attends the bi-weekly tumor immunology seminar series.

“These organizations have further enriched my experience at CU Anschutz,” said Winter. “They’ve given me unique perspective, knowledge and networking opportunities I wouldn’t have found elsewhere.”

CU Anschutz has also given him the opportunity to attend seminars, conferences and other events led by outstanding scientists. “Through these events, I’ve heard from some of the most prestigious scientists in the world – some of which are a part of this campus,” said Winter.

Looking forward

Winter wants to continue his educational career at CU Anschutz in either the Molecular Biology  PhD program or the Biomedical Sciences PhD program.

“I’ve learned so much in my time as a master’s student and research assistant,” said Winter. “As I near completion of my master’s degree in the BSBT program, I can look back at the previous year and say CU Anschutz was the right decision for me.”

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Rare brain donation could shed light on Alzheimer’s pathology

As he looks back on this year’s activities at the Rocky Mountain Alzheimer’s Disease Center, Huntington Potter, PhD, points to one event that was especially meaningful – receiving the center’s first brain donation for research from a person with Down syndrome who died with late-stage Alzheimer’s disease.

It’s a contribution neuroscience researchers hope will help further unravel the mystery of why some people develop Alzheimer’s disease symptoms while others do not.

Potter, whose groundbreaking research expanded knowledge of the genetic and molecular relationships between Alzheimer’s disease and Down syndrome, said the donation was made by a Denver-based family who felt that their sister would have been thrilled to know that she was making a significant contribution to science.

‘Great contribution’

And, Potter said, it’s a sentiment that goes beyond this one family. “People with Down syndrome and their families would very much like to help research to understand Alzheimer’s disease in them and in the rest of us, and so brain donations from people with Down syndrome are very important.”

“It’s a great contribution to humanity,” he added.

Potter plays multiple roles related to Alzheimer’s disease and Down syndrome research at the CU School of Medicine. In addition to being the Director of the Rocky Mountain Alzheimer’s Disease Center, he is also the Director of Alzheimer’s Disease Research at the Linda Crnic Institute for Down Syndrome.

The brain came from a 63-year-old woman named Gretchen Josephson, whose family has a long lineage in medicine and a connection to the CU School of Medicine. (See sidebar below).

Connection to Alzheimer’s disease

The direct link between Down syndrome and Alzheimer’s disease is on human Chromosome 21. People with Down syndrome are born with three copies of Chromosome 21 in every cell, a condition that occurs at conception.

Brain donor Gretchen Josephson
The brain donation came from Gretchen Josephson, second from left, a woman with Down syndrome. Josephson’s family has a long lineage in medicine. Here, she is pictured with her three sisters.

Additionally, the main gene that produces the protein linked to Alzheimer’s disease resides on Chromosome 21. Because people with Down syndrome have this third copy of Chromosome 21 in all of their cells, Potter says that they all will develop the underlying Alzheimer’s disease pathology by the time they are 40 years old.

According to Potter, the mystery is that despite all people with Down syndrome having this predisposition to Alzheimer’s disease brain pathology, around 20 percent will not develop dementia symptoms.

“We’d like to study them to better understand how Alzheimer’s disease brain pathology and dementia develop,” he said. “That way, we could learn who is most likely to develop dementia and who isn’t. And we’d like to be able to initiate treatment for people who don’t have Down syndrome but who might be at risk, say, in their 40s or 50s, and prevent the cell death and the problems that accompany Alzheimer’s disease.”

Potter points out that Alzheimer’s disease is believed to start developing as many as 20 years before clinical symptoms appear. He says the main research goal is to develop treatments for people “on the steps” to Alzheimer’s disease, and also to develop early diagnoses.

The vast majority of people who are diagnosed with typical age-related Alzheimer’s disease, over 95 percent, do not have Down syndrome. However, Potter’s earlier research showed that they have Down syndrome-like cells with three copies of Chromosome 21 throughout their bodies, including in neurons in their brains.

Insights into the pathology

“What are the earliest signals in people with Down syndrome that they’re going to develop Alzheimer’s disease within five or 10 years? Can we use those same signals, whether it be a blood protein or a neuropsychological test, to help figure out when and whether the rest of us are at risk for Alzheimer’s disease?”

In recent years, Alzheimer’s disease research centers around the world have received many brain donations from typical people with Alzheimer’s disease, but not from people with Down syndrome. These donations are very rare, and “are very valuable,” said Potter, “because if we can understand more about the pathology that develops in people with Down syndrome, we will be better able to understand the pathology that happens in typical people. And that’s going to give us a hint of what’s going wrong, and of how we might be able to compare the brains and come up with an idea for fixing them.”

Potter also notes that receiving a brain for research from a person with Down syndrome who did not have dementia at death would be especially rare and would be extremely valuable for research.

Potter encourages adults with Down syndrome to be assessed by the neurology team in the Memory Disorders Clinic, part of the Neurology clinic in the Anschutz Outpatient Pavilion and the clinical arm of the Rocky Mountain Alzheimer’s Disease Center. “We recommend this regardless of whether they have memory problems, so that they can take full advantage of the consultation opportunities,” he said.

More information about the center is at www.medschool.ucdenver.edu/alzheimers.

Guest Contributor: Both of these stories were written by Helen Gray, MBA, Communications and Community Outreach Coordinator of the Rocky Mountain Alzheimer’s Disease Center.

 

GRETCHEN JOSEPHSON MADE A ‘LAST GREAT GIFT TO ALL OF US’

The Denver woman with Down syndrome whose brain is the first donated for Alzheimer’s disease and Down syndrome research had a reputation for making her own way in the world and for making friends wherever she went.

Gretchen Josephson, who was 63 when she died, was the daughter of two physicians, the fourth of four girls. Her mother, Lula Lubchenco Josephson, MD, was a professor in the Department of Pediatrics in the CU School of Medicine. Her father, Carl Josephson, MD, was a cardiologist in private practice.

Gretchen graduated from South High in Denver Public Schools and studied food service at the Emily Griffith Opportunity School. The training helped her land a job as a bus girl at the Tea Room at the old downtown Denver Dry Goods store before it closed. Gretchen was retrained to work with inventory on the retail side of Foley’s, and then Macy’s at the Cherry Creek Mall. By the time she retired, Gretchen had worked continuously for 37 years.

And customers remembered Gretchen. Her eldest sister, Patty McFeeley, MD, said “you couldn’t walk with her through the Cherry Creek Mall without someone stopping her and saying, ‘Hi Gretchen.’”

Wrote a book of poetry

Gretchen wrote poetry. In 1997, with her mother’s encouragement, she published a book of poems called “Bus Girl,” and read and signed copies for a packed house at the Tattered Cover bookstore.

Gretchen Josephson with book of poetry
Gretchen Josephson holds “Bus Girl,” her book of poems.

One of Gretchen’s passions was country music. She frequently traveled to Nashville and figured out how to go backstage at concerts. The walls of Gretchen’s apartment were covered with photos of her and the stars she adored so much.

Another passion was sports. In addition to skiing, Gretchen swam and competed in Special Olympics. Her family took her on scuba trips, and her sister said she especially loved the shipwreck dives.

Self-advocate for Down syndrome

Gretchen was a self-advocate for Down syndrome, and she spoke at numerous national and international conferences, telling large audiences about her personal experiences with independent living.

McFeeley, a pathologist, said it was natural for Gretchen’s sisters to consider making the brain donation for scientific research. She occasionally took Gretchen along when she performed post-mortem examinations on cadavers, and Gretchen was, according to McFeeley, “fascinated” with the procedure.

Although Gretchen’s Alzheimer’s disease had advanced so much that she wasn’t able to discuss her own brain donation before she died, her sisters firmly believe that would have been what Gretchen wanted. “It was her last great gift to all of us,” said McFeeley.

 

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CU’s AIDS Clinical Trials Unit celebrates 25 years of progress

Diagnosed in 1991, David Dillon was sure his HIV-positive test was a death sentence. He’d watched friends die, struggling on the only drugs available at the time, medications that had intense side effects and were barely effective, with the rapidly evolving AIDS virus building resistance to them often within months.

But then the words of a social worker resonated in his mind. Experts, she had told him soon after hearing his diagnosis, were on the verge of turning the once always-deadly affliction into a chronic but manageable disease. “That’s what I grabbed on to right away,” Dillon said. “And that’s what I’ve hung on to ever since.”

Dillon was one of the first HIV-positive patients to volunteer for studies with the AIDS Clinical Trials Unit (ACTU) at the now University of Colorado Anschutz Medical Campus. Today, as the ACTU celebrates 25 years of major contributions in revolutionizing HIV/AIDS treatment, Dillon is still alive, grateful for CU and content knowing he helped make a difference.

Creating a top-notch program

The human-immunodeficiency virus (HIV), which spread fear and bias throughout the country in the ‘80s, killing people from actor Rock Hudson to writer Isaac Asimov, had no treatment until 1987, and no effective drugs until the mid-‘90s. CU eventually became one of the top research universities for HIV/AIDS research in the world, but not until netting a major new faculty recruitment.

AIDS patient David Dillon
David Dillon has set a goal of outliving his new pup, Finn.

“It was a big deal,” Thomas Campbell, MD, principal investigator of CU’s ACTU, said of the 1989 recruitment of Robert “Chip” Schooley. A Harvard Medical School professor and prominent, internationally-recognized HIV researcher, Schooley established CU as an AIDS Clinical Trials Center, bringing front-line drugs to the region.

“I remember sitting on my back porch and reading about his recruitment on the front page of The Denver Post,” said Campbell, who was an infectious disease fellow at the time. “Bringing him to Colorado was like recruiting John Elway to the Denver Broncos. It’s bringing a superstar to Colorado, which helps elevate the whole team.”

By 1991, when Dillon, a Housing Department employee at CU Boulder at the time, was learning of his infection, the National Institutes of Health was tapping Schooley to lead a new ACTU, injecting $4.8 million in adult AIDS research and $3 million in pediatric AIDS research into CU’s coffers. CU’s unit joined a growing number of national sites within the AIDS Clinical Trials Group (ACTG), formed in 1986 as the urgency for new drugs intensified.

“Schooley was the key person that made that happen, and so all of the great HIV/AIDS research capacity that we have today is largely possible because of the groundwork that he laid and the foundation that he built in the early ‘90s,” said Campbell, who had joined CU as an infectious disease fellow that year and is now medical director of the adult Clinical and Translational Research Center (CTRC) of the Colorado Clinical Translational Science Institute at CU, where clinical trials are conducted.

For many Colorado HIV patients, including Dillon, the move was a life-saving boon.

Road past resistance is long

Wearing a beeper, which interrupted him every four hours to take his arsenal of pills, Dillon, now 65, was one of the lucky ones in that the regimen’s side effects didn’t make him so sick he ditched the AZT (azidothymidine), choosing to accept HIV’s fate. But he knew the drug’s effects were waning.

‘It seemed like I was already at the cusp, so when a drug came into testing, I was ready for it. Dr. Steven Johnson saved my life more than once.’ – patient David Dillon

Dillon found Graham Ray, RN, still a study coordinator with CU’s ACTU, and signed up for one of the first of what would exceed 177 clinical trials in the unit’s 25 years, with more than 2,500 participants coming forward to help scientists in their search for a more effective treatment.

The study involved spending some nights in the hospital, and Dillon recalled a trial patient in a nearby bed. “He had pretty much run the gamut of drugs available. He’d run out of options, so this trial was one of his last hopes,” Dillon said. “I lost several friends that were in the same boat. There just wasn’t new treatment coming fast enough to help them.”

Few drugs and rapid resistance were major problems for patients in those days,” Campbell said. “We could only give one or two drugs at the most together, and drug resistance developed very rapidly. The medicines lost their effectiveness.”

For Dillon, who estimates he tried upwards of 20 single experimental drugs, the trials always came right in time, with Ray and his CU doctor, Steven Johnson, MD, of the Division of Infectious Diseases, regularly alerting him to new studies.

“It just seemed like I was already right at the cusp, so when a drug came into testing, I was ready for it,” said Dillon, who still travels to CU Anschutz from his Loveland home, indebted to his caregivers. “Dr. Johnson saved my life more than once,” said Dillon, who has AIDS, the end-stage disease of an HIV infection.

HIV attacks patients’ immune systems by binding to and killing CD4 cells, which are largely responsible for fighting infections. Doctors monitor CD4-cell counts, assessing the progression of the disease. If a patient’s count falls below 200, then they are diagnosed with AIDS, and their risk of deadly infections rises. Dillon’s counts were once as low as five.

Trial volunteers join mission

AIDS patient Patrick Terry
Patrick Terry has been an integral member of the International Gay Rodeo Association for 30 years.

For Patrick Terry, a former Colorado rodeo staple and Denver-area native, who has done “probably a dozen” trials with CU since 2000, taking part in trials is about staving off AIDS (his CD4 count has never fallen below 500), and putting an end to the epidemic. “To me, it’s so important that we find out more about it, and if there’s any chance that there could be a cure, then I’d like to be a part of it.”

Helping science isn’t always easy, said Dillon and Terry, 60, who calls himself a go-to volunteer for ACTU research nurse Cathi Basler, RN, because of his dedication to the trial process. Although he said he’s “lucky” to have apparently always received the active drug in the double-blind studies, Dillon recalled a nearly five-year trial that required injecting a drug in his abdominal muscles twice a day.  “It just hurt, and you had to just keep doing it.”

“You know when you are on the real drug,” said Terry, who has volunteered for clinical trials with Basler for years after being diagnosed with HIV in 1995. “I’ve had some very difficult studies,” he said, noting one in which the drug was so strong, it caused hallucinations, and another in which he had to have lymph nodes removed.

But the pair’s dedication has paid off, for them, and for many of the more than 30 million people worldwide living with HIV.

Treatment only works with adherence

In 1996, a CU ACTU-led research study played a key role in the development and widespread use of what was commonly termed “drug cocktails.” That was a major turning point in HIV/AIDS treatment, Campbell said.

“When we first really had the ability to put three drugs together to make an effective combination, it greatly reduced the risk of drug resistance. It did so by having much more effective suppression of viral replication,” he said. “We suddenly had a way to effectively treat HIV and prevent all the damage it does to the body.”

AIDS patient David Dillon at CU Anschutz
David Dillon, one of the first HIV-positive patients to volunteer for studies with the AIDS Clinical Trials Unit, is indebted to his caregivers at the CU Anschutz Medical Campus. He still travels regularly to CU Anschutz from his home in Loveland.

Part of a two-drug combination trial today, Terry’s CD4 counts hover around 1,000, and his viral load is undetectable. For, Dillon, although his CD4 counts aren’t quite so high, and his “cocktail” includes five drugs, his viral load is also undetectable.

But Terry, emphasizing that the effective drugs are still not a cure, advocates for medication adherence. “I’ve never missed a dose, and that’s probably one of the most important things,” said Terry, , who watched his “little brother” die in 2005, after living in denial with an HIV infection for years and succumbing to AIDS within 18 days of hospitalization.

“Take it seriously,” Terry said. “Don’t skip your medicine. That’s a problem with so many people. The medicine doesn’t work if you don’t take it. And take care of yourself,” he said, adding that he stopped drinking at diagnosis and keeps an eye on fitness.

Workload for researchers still great

While noting the great scientific achievements, which would not have been possible without dedicated volunteers, Campbell, too, emphasized that HIV remains a serious virus with no cure. “Yes, a person diagnosed today who seeks treatment early and adheres to it should live a near-normal lifespan,” Campbell said. “But near normal is not normal. There’s still a lot of work that needs to be done.”

The to-do list for HIV/AIDS researchers remains long, with vaccine trials still underway, and development of a cure feasible but probably not within close reach, Campbell said. Continuing efforts to treat HIV patients in developing countries remains a priority, as does boosting prevention education.

For instance, use of an antiretroviral drug combination called PrEP in high-risk individuals who are not yet infected can reduce their chances of contracting HIV, and early treatment in patients already infected can not only boost their chances of success; it reduces the virus’s spread, Campbell said. “So we not only help them, but we help the rest of the community.”

Dillon said he’s grateful for that first social worker’s hopeful words and for finding the ACTU at CU at the right time. “It saved my life, and it saved a lot of other lives.”

Photo at top: Constance Benson, MD, Robert “Chip” Schooley, MD, and Thomas Campbell, MD, attended a recent Zimbabwe Art and Sculpture Auction in the Fulginiti Pavilion.

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Skin pigmentation far more complex than previously known

Researchers examining understudied populations in Africa have found that skin pigmentation is far more varied and complex than previously understood. And that complexity increases nearer the equator.

Associate Professor Chris Gignoux of the Colorado Center for Personalized Medicine is co-author of
Associate Professor Chris Gignoux of the Colorado Center for Personalized Medicine at CU Anschutzx is co-author of the study.

“Previous studies have focused on more homogeneous European and Eurasian populations and concluded that pigmentation was governed by just a handful of genes,” said study co-author Christopher Gignoux, PhD, MS, associate professor at the Colorado Center for Personalized Medicine at the University of Colorado Anschutz Medical Campus. “But in this study we looked at pigmentation among African populations and found a striking variability that has been underappreciated.”

The study, published in the November edition of the journal Cell, is the culmination of a decade’s worth of research involving scientists from CU Anschutz, the State University of New York at Stony Brook, Stanford University, Stellenbosch University, and the Broad Institute of MIT and Harvard.

The researchers studied two populations of the KhoeSan people, the Khomani San and the Nama. Both live in South Africa and have much lighter skin than other Africans who live closer to the equator.

Scientists conducted interviews, recorded height, age and gender and used a reflectometer to measure skin color of about 400 people. They discovered that skin pigmentation is highly heritable but that doesn’t explain its variance and complexity. Instead of a few genes controlling the process as many thought, they found far more genes involved, each one contributing something different. And many of the genes have yet to be discovered. Only about 10 percent of that previously discovered variation can be linked to genes impacting pigmentation in the KhoeSan.

One finding showed that the closer a population moves to the equator, the more genes come into play that can influence variability.

“Light skin pigmentation in the KhoeSan appears to be due to a combination of many small-effect mutations as well as some large-effect variants,” said the study’s senior author Brenna Henn, assistant professor of ecology and evolution at SUNY Stony Brook.

Some of those mutations, Henn said, may have arisen in southern Africa more than 100,000 years ago and were selected for in Europeans after they left Africa for higher latitudes where pigment lightens to absorb more sunlight which produces vitamin D and folate protection.

The researchers studied two populations of the KhoeSan people, the Khomani San and the Nama. Both live in South Africa
The researchers studied two populations of the KhoeSan people, the Khomani San and the Nama. Both live in South Africa.

“We argue that the distributions of skin pigmentation globally suggest different forces of selection operating at various latitudes,” Henn said.

In order to understand baseline pigmentation, she said, it’s important to study a large set of genetically diverse populations that have historically been exposed to different levels of ultraviolet radiation.

Gignoux agreed saying earlier notions of skin pigmentation being relatively simple underestimated the genetics involved.

“At higher latitudes there is far less difference in skin pigmentation and that’s where most of the earlier research was done,” he said. “But there is more pigmentation variation on the African continent than any other place on earth and its needs further study.”

 

 

 

 

 

 

 

 

 

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