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Overcoming a health challenge and finding purpose

Seven years ago, Courtland Keteyian rolled into an operating room, excited by the prospect of running the way he once did as a star athlete on the track team in college. He imagined running on an outdoor trail and alongside gurneys in an emergency room.

Post-surgery, a few hours later, nurses wheeled him out of the operating room. He has been in a wheelchair ever since.

His surgeon made the operation sound fairly routine. A first-year resident at the time, studying emergency medicine, Keteyian was aware of the litany of things that can go wrong on the operating table. But he went in with confidence and assurances that the risks of the operation were minimal. He felt certain that his bothersome running injury would finally be healed.

But after this surgery, he could not even walk.

Finding meaning in work

Keteyian admits that dealing with the complications of his surgery was not easy. But instead of turning away from medicine, his desire to become a doctor grew stronger. He decided he wanted to become a different kind of doctor — one focused on prevention and who avoids unnecessary medical interventions as much as possible.

He finished his internship in emergency medicine and went on to complete his residency in preventive medicine at the University of Michigan. Today, he is an occupational and environmental medicine fellow at the Colorado School of Public Health (ColoradoSPH) on the CU Anschutz Medical Campus.

With BS, MD, MBA, and MPH degrees, experience as the CEO of his own startup company, and time spent as the medical director of a county health department under his belt, Keteyian brings a unique set of skills to the fellowship. He is the first fellow to matriculate into the program, one of the only one-year fellowships in the country that offers a path for physicians to become board certified in occupational medicine. The program was designed by faculty in the ColoradoSPH’s Center for Health, Work & Environment and is funded by the center’s Mountain & Plains Education and Research Center and an educational grant from Pinnacol Assurance, the largest workers’ compensation insurer in Colorado.

“I take a lot of pride in going to work each day. I think most people do. I wanted to work with people who experience disability and help them be functional at work so they can continue to experience that sense of value,” said Keteyian.

While his current career path is not exactly what he would have imagined as an intern at the University of Michigan, he has found purpose. Specializing in occupational medicine has offered him the opportunity to help others overcome their health challenges, get back to work, and hopefully regain the sense of identity that their job symbolizes.

Prevention-first approach

The fact that he was able to customize the program to fit his career goals, focus on his interest in prevention, and gain hands-on training in a clinical setting was a major draw of the fellowship.

When he is not treating patients, Keteyian is conducting research that will help prevent injuries and illnesses from occurring in the first place. Currently, he is investigating what factors cause repeat job-related injuries by analyzing workers’ compensation claims. He and his co-investigators in the Center for Heath, Work & Environment envision using the findings of this work to help employers and employees prevent repeat injuries, a topic that has not been studied extensively in the past.

“Seeing patients is important work, but it’s impact is mainly limited to the present,” said Keteyian. “It is critically important to understand why workers experience injuries and what can be done to prevent them. Research is essential to answer this question, and has the potential to improve health outcomes for workers long into the future.”

Connecting with patients who experience disability

Keteyian’s experiences as a frustrated patient and as a physician with a disability have informed both his research focus on prevention as well as his interactions with patients.

“Regardless of who the patient is, I think just seeing someone in a wheelchair can be very disarming for patients,” he said. “It can create a bridge that wasn’t there before. They think, ‘This guy gets it. He’s had some sort of challenge.’”

After years of hard work, Keteyian is now able to walk to some extent. But most of his time is spent in a wheelchair. The way Keteyian sees it, everyone will cope with disability in their lifetime in some way. Our ability to do everyday activities, on the job or at home, may change over time. Keteyian often conveys to patients that they are not alone in facing challenges and that they can still contribute to society, even if they need to adjust their work tasks or lifestyle to accommodate an illness or injury.

“Just because you have an injury or a disability doesn’t mean you can’t be very productive in other ways,” said Keteyian. “I treat patients and do research to contribute in ways that I feel are meaningful to society.”

The combination of Keteyian’s background in emergency medicine and his own personal health journey has led him down a career path focused on prevention and helping workers. He looks forward to continuing to build on his clinical and research expertise to move prevention-first approaches forward in the field of occupational and environmental medicine.

Learn more about the fellowship and how to apply. 

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Existing drug may be effective at preventing onset of type 1 diabetes

A drug commonly used to control high blood pressure may also help prevent the onset of Type 1 diabetes in up to 60 percent of those at risk for the disease, according to researchers at the University of Colorado Anschutz Medical Campus and the University of Florida (UF) in Gainesville.

The study was published online this week in the Journal of Clinical Investigation.

Dr. Aaron Michels of the Barbara Davis Center for Childhood Diabetes.
Dr. Aaron Michels of the Barbara Davis Center for Childhood Diabetes.

“This is the first personalized treatment for Type 1 diabetes prevention,” said Aaron Michels, MD, a researcher at the Barbara Davis Center for Childhood Diabetes and associate professor of medicine at CU Anschutz. “We made this discovery using a supercomputer, on the lab bench, in mice and in humans.”

The drug, methyldopa, has been used for over 50 years to treat high blood pressure in pregnant women and children. It is on the World Health Organization’s list of essential drugs.

But like many drugs used for one condition, Michels and his colleagues found it useful for something totally unrelated.

Molecule blocking

Some 60 percent of people at risk of getting Type 1 diabetes possess the DQ8 molecule which significantly increases the chance of getting the disease. The researchers believed that if they could block specifically the DQ8 molecule they could also block the onset of the disease.

“All drugs have off-target effects. If you take too much acetaminophen you can hurt your liver,” Michels said. “We took every FDA-approved small molecule drug and analyzed HLA-DQ8 binding through a supercomputer. We searched a thousand orientations for each drug to identify those that would fit within the DQ8 molecule binding groove.”

After running thousands of drugs through the supercomputer, they found that methyldopa not only blocked DQ8, but it didn’t harm the immune function of other cells like many immunosuppressant drugs do.

The research spanned 10 years and its efficacy was shown in mice and in 20 Type 1 diabetes patients who took part in a clinical trial at the Barbara Davis Center at the University of Colorado School of Medicine.

“We can now predict with almost 100 percent accuracy who is likely to get Type 1 diabetes,” Michels said. “The goal with this drug is to delay or prevent the onset of the disease among those at risk.”

The drug is taken orally, three times a day.

Implications for treatment

Michels and UF Health researcher David Ostrov, PhD, hope this same approach of blocking specific molecules can be used in other diseases.

“This study has significant implications for treatment of diabetes and also other autoimmune diseases,” said Ostrov, associate professor of pathology, immunology and laboratory medicine in the UF College of Medicine and a member of the UF Health Cancer Center, Genetics Institute and Center for NeuroGenetics. “This study suggests that the same approach may be adapted to prevent autoimmune diseases such as rheumatoid arthritis, coeliac disease, multiple sclerosis, systemic lupus erythematosus and others.”

The next step will be a larger clinical trial sponsored by the National Institutes of Health in spring.

“With this drug, we can potentially prevent up to 60 percent of Type 1 diabetes in those at risk for the disease,” Michels said. “This is very significant development.”

The other authors include: Aimon Alkanani of the Barbara Davis Center at CU Anschutz; Kristen McDaniel of the Barbara Davis Center; David Ostrov of the University of Florida in Gainesville; Stephanie Case of the Barbara Davis Center; Erin Baschal of the Barbara Davis Center; Laura Pyle of the Barbara Davis Center and Colorado School of Public Health; Sam Ellis of the Barbara Davis Center and Dept. of Clinical Pharmacy at CU Anschutz; Bernadette Pollinger at the Novartis Institutes for Biomedical Research in Basel, Switzerland; Katherine Seidl at Novartis; Viral Shah at the Barbara Davis Center; Satish Garg at the Barbara Davis Center; Mark Atkinson at the University of Florida and Peter Gottlieb at the Barbara Davis Center.

 

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Immune system dysfunction may occur early in Alzheimer’s disease

An association between inflammation biomarkers in both blood plasma and cerebrospinal fluid (CSF) and markers of Alzheimer’s disease (AD) associated pathology, has been found by researchers at the University of Colorado Anschutz Medical Campus working with the University of Wisconsin Alzheimer’s Disease Research Center and the University of California San Francisco Memory and Aging Center.

The discovery sheds new light on the pathology of AD as well as on the communication between the brain and the rest of the body. The findings were published today in the Journal of Alzheimer’s Disease.

Brianne Bettcher, PhD, assistant professor of neurosurgery and neurology at CU Anschutz
Brianne Bettcher, PhD, assistant professor of neurosurgery and neurology at CU Anschutz.

Scientists have long known that AD-related pathology may develop long before clinical symptoms of AD appear, and that inflammation is a core component of the disease. Previous studies have linked levels of inflammatory markers in CSF and blood to Mild Cognitive Impairment (MCI), and research shows that elevations in inflammatory markers may be present decades before any AD symptoms appear.

However, whether markers of inflammation in the blood (i.e., ‘peripheral’ inflammation) were related to known measures of AD-related pathology, even after accounting for CSF levels of inflammation (i.e., ‘central’ inflammation), remained unclear. Researchers also wanted to know whether markers of inflammation in blood plasma reflected inflammation of the central nervous system.

“One of the two primary goals of our study was to assess the association between inflammatory markers in CSF and plasma to clarify how well plasma inflammatory markers reflect central nervous system inflammation,” said study author Brianne Bettcher, PhD, assistant professor of neurosurgery and neurology at the University of Colorado School of Medicine. “Even more importantly, we were interested in determining whether inflammatory markers in plasma were independently linked to CSF markers of AD-related pathology and neuronal damage in a group of healthy, community dwelling older adults.”

Her team tested blood and CSF samples from 173 middle-aged and older adults enrolled in the Wisconsin Alzheimer’s Disease Research Center. Participants were healthy adults in that they had no clinical symptoms of Alzheimer’s disease, although some had family histories of dementia presumed due to AD.

The scientists had expected inflammation markers in the CSF to be more robust predictors of AD-related pathology and neuronal damage than those in the blood due to the `blood brain barrier.’

“Results from our study suggest that although CSF markers of inflammation are strong predictors, both plasma and CSF markers of inflammation independently relay information about AD-related pathology and neuronal damage in head-to-head comparisons,” Bettcher said.

The finding was unexpected.

“From my perspective, there has been a perception in the field that the blood and the ‘periphery’ are not related to the brain – that the brain and the rest of the body are completely separate,” Bettcher said. “I think increasing evidence suggests that the brain and body communicate. Our study shows that inflammation markers in the blood may be telling us about what is going on inside the brain.”

Recent animal studies have shown a strong relationship between elevated inflammation and the propagation of tau proteins, which are associated with AD.

Bettcher said the new findings could possibly serve as the focus of more in-depth studies aimed at developing a blood test to detect inflammation biomarkers years before symptoms of Alzheimer’s appear.

She says the study also points to a potentially early role for inflammation in aging and AD. Bettcher also emphasized that although participants had detectable levels of AD-related markers and markers of neuronal damage in their CSF, the presence of these markers alone does not indicate a diagnosis of AD, nor does it mean that they will develop AD in the future.

“These findings add to a growing body of literature underscoring an increasingly important relationship between systemic inflammation, central inflammation, and pathological outcomes,” she said.

Full Reference:
Bettcher, B.M., Johnson, S.C., Fitch, R., Casaletto, K.B., Heffernan, K.S., Asthana, S., Zetterberg, H., Blennow, K., Carlsson, C.M., Neuhaus, J., Bendlin, B.B., & Kramer, J.H. (2018). Cerebrospinal fluid and plasma levels of inflammation differentially relate to CNS markers of Alzheimer’s disease pathology and neuronal damage. Journal of Alzheimer’s Disease, 62(1). DOI 10.3233/JAD-170602

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Powerful food-derived antioxidant can halt, prevent fatty liver disease

As obesity continues to rise in the U.S., non-alcoholic fatty liver disease (NAFLD) has become a major public health issue, increasingly leading to cancer and liver transplants.

But new research from the University of Colorado Anschutz Medical Campus has discovered that a powerful antioxidant found in kiwi fruit, parsley, celery and papaya known as pyrroloquinoline quinone, or PQQ, can halt or prevent the progression of fatty liver disease in the offspring of mice fed a high-fat Western-style diet.

Dr. Karen Jonscher
Karen Jonscher, PhD, associate professor of anesthesiology and a physicist at CU Anschutz.

Growing evidence suggests that childhood obesity and fatty liver disease is influenced by maternal diet and the infant’s microbiome, the community of microorganisms inhabiting the body.

Jonscher and her colleagues found that mother mice fed a Western-style diet passed on the negative impacts of that diet to their offspring.

Jonscher’s earlier work on PQQ showed it helped turn back these detrimental effects in newborn mice in milder forms of liver disease. In this study, she demonstrated that it also works on the early offspring microbiome to prevent the development of fatty liver disease.

Over the past decade, it has become clear that the developing infant gut microbiome affects maturation of the immune system and gastrointestinal tract, metabolism, and brain development.

“Increasingly, evidence suggests that exposure to maternal obesity creates an inflammatory environment in utero. This leads to long-lasting postnatal disruptions of the offspring’s innate immune system and gut bacterial health, which may increase the risk for development of fatty liver disease,” Jonscher said.

Obesity, which often stems from a high-fat, high-cholesterol, sugary diet, is a major cause of NAFLD. According to the Journal of the American Medical Association, nearly 60 percent of American women of childbearing age are overweight or obese. Numerous studies suggest their children tend to have increased liver fat and a higher risk of becoming obese.

Kiwi fruit, among others, contains a powerful antioxidant shown to halt or prevent fatty liver disease in young mice.
Kiwi fruit, among others, contains a powerful antioxidant shown to halt or prevent fatty liver disease in young mice.

“Fatty liver disease is the number one liver disease in the world,” Jonscher said. “It is now the leading cause of liver transplants, eclipsing hepatitis in many areas of the U.S.”

The researchers found that they could halt and prevent liver disease from developing in young mice by feeding their mothers PQQ.

“Our results highlight the importance of the neonatal period as a critical developmental window to protect obese offspring from the harmful effects of diet-induced lipotoxicity and potentially halt the devastating trend of increasing pediatric NAFLD associated with childhood obesity,” the study said.

Jonscher noted that more work is required to determine if these studies might apply to humans.

“But there is a possibility that people with fatty liver disease could potentially benefit,” she said. “The supplement is available online and in grocery stores but individuals should consult their doctors first before using it.”

 

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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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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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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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CU School of Medicine Physician Receives Top Honor

Michael Holers, MD, the Scoville Professor of Rheumatology in the University of Colorado School of Medicine, was honored with the designation of Master by the American College of Rheumatology (ACR) during the 2017 ACR/ARHP Annual Meeting in San Diego. Recognition as a Master is one of the highest honors that the ACR bestows on its distinguished members.

Dr. Michael Holers
Dr. Michael Holers

The designation of Master is conferred on senior ACR members who have made outstanding contributions to the field of rheumatology through scholarly achievement and/or service to their patients, students, and the rheumatology profession. Honorees have devoted their careers to furthering rheumatology research and improving clinical standards in the treatment of rheumatic diseases.

“It’s an honor to be recognized for my commitment to advancing research in the field of rheumatology that is focused on improving treatment and developing novel prevention strategies,” said Dr. Holers. “I am truly humbled to receive this designation and join the ranks of my distinguished rheumatology colleagues.”

ACR Masters must be highly accomplished individuals. Evidence of their achievements can come from many types of endeavors and honors, such as research, education, health care initiatives, volunteerism, and administrative positions. The Master must be distinguished by the excellence and significance of his or her contributions to the science and art of rheumatology.

Holers began his academic career at Purdue University and then continued as a medical student in the School of Medicine of Washington University in St. Louis. Following medical school, he was an intern and resident at Barnes Hospital in St. Louis and then a Rheumatology Fellow for two years at the University of Colorado. There he got his first research experience, discovering and publishing on the presence of nuclear antigens on the surfaces of activated cells. Following this introduction to research, Holers sought an intensive research training experience and undertook a wet bench postdoctoral fellowship at Washington University. Following successful conclusion of that position, he began his independent research career there as an Assistant Professor of Medicine and Howard Hughes Assistant Investigator.

After Holers achieved the academic level of Associate Professor with tenure, he was recruited in 1993 by Drs. Robert Schrier and Bill Arend to the University of Colorado as the first Smyth Professor of Rheumatology. Holers was subsequently promoted to Professor of Medicine and Immunology. In 2000, he was named the Division Head of Rheumatology and then in 2008 the Scoville Professor of Rheumatology, positions which he has held to the current period.

For more information on each of these awards, and to view past recipients, please visit www.rheumatology.org/Get-Involved/Awards.

 

 

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University of Colorado School of Medicine Physician Receives Top Honor

Dr. Michael Holers, the Scoville Professor of Rheumatology in the University of Colorado School of Medicine, was honored with the designation of Master by the American College of Rheumatology (ACR) during the 2017 ACR/ARHP Annual Meeting in San Diego. Recognition as a Master is one of the highest honors that the ACR bestows on its distinguished members.

Dr. Michael Holers
Dr. Michael Holers

The designation of Master is conferred on senior ACR members who have made outstanding contributions to the field of rheumatology through scholarly achievement and/or service to their patients, students, and the rheumatology profession. Honorees have devoted their careers to furthering rheumatology research and improving clinical standards in the treatment of rheumatic diseases.

“It’s an honor to be recognized for my commitment to advancing research in the field of rheumatology that is focused on improving treatment and developing novel prevention strategies,” said Dr. Holers. “I am truly humbled to receive this designation and join the ranks of my distinguished rheumatology colleagues.”

ACR Masters must be highly accomplished individuals. Evidence of their achievements can come from many types of endeavors and honors, such as research, education, health care initiatives, volunteerism, and administrative positions. The Master must be distinguished by the excellence and significance of his or her contributions to the science and art of rheumatology.

Dr. Holers began his academic career at Purdue University and then continued as a medical student in the School of Medicine of Washington University in St. Louis. Following medical school, he was an intern and resident at Barnes Hospital in St. Louis and then a Rheumatology Fellow for two years at the University of Colorado. There he got his first research experience, discovering and publishing on the presence of nuclear antigens on the surfaces of activated cells. Following this introduction to research, Dr. Holers sought an intensive research training experience and undertook a wet bench postdoctoral fellowship at Washington University. Following successful conclusion of that position, he began his independent research career there as an Assistant Professor of Medicine and Howard Hughes Assistant Investigator. After Dr. Holers achieved the academic level of Associate Professor with tenure, he was recruited in 1993 by Drs. Robert Schrier and Bill Arend to the University of Colorado as the first Smyth Professor of Rheumatology. Dr. Holers was subsequently promoted to Professor of Medicine and Immunology. In 2000, he was named the Division Head of Rheumatology and then in 2008 the Scoville Professor of Rheumatology, positions which he has held to the current period.

For more information on each of these awards, and to view past recipients, please visit www.rheumatology.org/Get-Involved/Awards.

 

 

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Scientists develop new theory of molecular evolution

Researchers from the University of Colorado Anschutz Medical Campus and the University College London have developed a new theory of molecular evolution, offering insights into how genes function, how the rates of evolutionary divergence can be predicted, and how harmful mutations arise at a basic level.

“Molecules are the basis of all life and we wanted to find out why molecules evolve the way they do,” said study co-author David Pollock, PhD, professor of biochemistry and molecular genetics at the CU School of Medicine.

Professor David Pollock, PhD, is co-author of the new study
Professor David Pollock, PhD, is co-author of the new study

Pollock and fellow author Richard Goldstein, Ph.D., professor of infection and immunity at University College London, published the study October 23, 2017 in the journal Nature Ecology and Evolution.

Their theory of evolutionary mechanics transforms evolving molecular systems into a framework where the tools of statistical mechanics can be applied, opening a novel window into how protein evolution works.

“The approach rests on understanding proteins as integrated systems,” said Goldstein. “Too often we ignore interactions between different parts of a protein, but we know that changes in one part of the protein affect subsequent changes in other parts. It turns out this is really important for understanding why these molecules evolve the way they do.”

Proteins constantly change as mutations become fixed or eliminated depending on the protein structure, function and stability. This depends on amino acid interactions throughout the protein that cause evolution at one site to alter the chance of evolution at other sites.

The scientists discovered that they could predict rates of protein evolution based on their biochemical properties.

“This was a real surprise,” Pollock said. “Our theory accounts for well-known population genetics effects such as strength of selection and effective population size, but they drop out of the final equations that predict the rate of molecular evolution.”

For years, researchers have run up against problems with standard models of molecular evolution used in studying the evolutionary relationships among species. This led to difficulties in reconstructing important evolutionary events in ancestral organisms.

These patterns of molecular convergence were found to change regularly over evolutionary time in ways that indicated continually fluctuating constraints in different parts of proteins.

“This flips around the usual idea that the amino acids will adjust to the requirements of the rest of the protein,” Goldstein said. “But we couldn’t explain exactly why this happened, or whether there was any regularity to the process.”

But once the system was placed into a statistical mechanics framework, the magnitude of amino acid entrenchment was seen as central to understanding rates of evolutionary divergence.

The researchers said that the strength of selection in protein evolution is balanced by the sequence entropy of folding, the number of sequences that provide a protein with a given degree of stability.

“We like to think of the other amino acids as a bunch of kids jumping down on a memory foam mattress while you try to walk on it,” Pollock said. “Most of the time your feet are sunk into the mattress and you can’t step forward, but every so often the kids will create a dent in the mattress that allows you to step ahead.”

The title of the paper is “Sequence entropy of folding and the absolute rate of amino acid substitutions.”

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