Scientists at the University of Colorado Anschutz Medical Campus have implicated a largely hidden part of the human genome in the severity of autism symptoms, a discovery that could lead to new insights into the disorder and eventually to clinical therapies for the condition.
The researchers found the critical genes are a part of the human genome that is so complex and difficult to study that it has been unexamined by conventional genome analysis methods.
In this case, the region encodes most copies of the Olduvai (formerly DUF1220) protein domain, a highly duplicated (~300 copies in the human genome) and highly variable gene coding family that has been implicated in both human brain evolution and cognitive disease.
The researchers, led by James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics at the University of Colorado School of Medicine, analyzed the genomes of individuals with autism and showed that, as the number of copies of Olduvai increased, the severity of autism symptoms became worse.
While the Sikela lab has shown this same trend previously, the discovery has not been pursued by other researchers due to the complexity of the Olduvai family.
“It took us several years to develop accurate methods for studying these sequences, so we fully understand why other groups have not joined in.” Sikela said. “We hope that by showing that the link with autism severity holds up in three independent studies, we will prompt other autism researchers to examine this complex family.”
In order to provide more evidence that the association with autism severity is real, the Sikela lab used an independent population and developed a different, higher resolution measurement technique. This new method also allowed them to zero in on which members of the large Olduvai family may be driving the link with autism.
Though autism is thought to have a significant genetic component, conventional genetic studies have come up short in efforts to explain this contribution, Sikela said.
“The current study adds further support to the possibility that this lack of success may be because the key contributors to autism involve difficult-to-measure, highly duplicated and highly variable sequences, such as those encoding the Olduvai family, and, as a result, have never been directly measured in other studies of autism,” Sikela said.
The study was published today in the American Journal of Psychiatry, and included CU Anschutz co-authors Jonathan M. Davis, PhD and Ilea Heft, PhD. Work was performed in collaboration with Dr. Stephen Scherer of The Hospital for Sick Children (SickKids) and University of Toronto and used whole genome sequences generated by the Autism Speaks MSSNG Open Science project. The work was supported by grants from the National Institute for Mental Health (NIMH) and the Simons Foundation for Autism Research (SFARI).
The Culinary Medicine Series features weekly cooking demonstrations of recipes that are healthy and nutritious for those with chronic illnesses such as cardiovascular disease, diabetes and cancer.
Lisa Wingrove, RD, CSO, a registered dietitian who specializes in nutrition for oncology patients, recently led a session on how to make a butternut squash mac-and-cheese dish geared for cancer patients. She shared basic cooking techniques and other methods for cooking for those with cancer.
“When someone has cancer or is going through chemotherapy treatment, sometimes the foods they liked before are not appealing anymore because certain smells become unappetizing,” said Wingrove.
What is Culinary Medicine?
As a new evidence-based field, culinary medicine blends cooking and medicine to help people access high-quality meals that help to prevent and treat disease. The Culinary Medicine Series, created in partnership with the UCHealth Digestive Health Center, the Integrative Medicine Center and the CU School of Medicine’s Department of Internal Medicine, provides members of the Aurora community as well as faculty, staff and students of CU Anschutz with nutrition resources.
“Many of the attendees of the classes are caregivers, patients or members of the community as well as staff or students on campus,” said Wingrove.
The concept of culinary medicine was created by John La Puma, MD, a physician who recognized a need for further nutrition education for both physicians and patients. According to La Puma, physicians need to learn how to prescribe food as medicine, and patients should become more educated about what foods can help beat disease.
“Many physicians don’t learn about nutrition in medical school, but it is something that can help people live better with chronic illness,” explained Wingrove.
Learning about nutrition
The Culinary Medicine Series gives anyone the knowledge to eat well and provides a resource to those struggling with chronic illness. “Nutrition is an evidence-based science, so we offer recipes that are beneficial to those living with chronic illness,” she said.
According to Wingrove, the recipes taught are alternatives to classic recipes and are meant to be more palatable for those with additional dietary restrictions.
“One of the goals of the sessions is to provide participants with alternatives while maintaining the flavor of their favorite dishes. A lot of the foods we cook include ingredients that you might already have in your kitchen,” said Wingrove.
The sessions are also intended to be interactive, giving participants opportunities to ask a dietitian questions.
“People come here who have never cooked before,” said Wingrove. “We want to make this an approachable environment where participants can feel comfortable asking us questions so they can learn new skills.”
As medicine continues to advance, so will treatment options. According to Wingrove, it will become more important to incorporate nutrition into treatment plans for patients with chronic illness.
“A lot can be gained from using nutrition as a treatment. For cancer, that means providing patients with a plant-based diet with lean proteins and helping maintain a healthy body weight,” said Wingrove.
The next class for cancer care in the Culinary Medicine Series taught by Lisa Wingrove takes place on March 12. To register, visit the series website.
For the butternut squash mac-and-cheese recipe, click here.
Aha! Eureka! The sounds of scientific breakthroughs echo across the University of Colorado Anschutz Medical Campus. While academia produces revolutionary ideas, it can be a complicated and difficult process to translate them to commercial products.
Fortunately, SPARK Colorado is here to help. The SPARK program works to bridge the world of academia with product development and business.
Bridging academia and industry
SPARK, which originated at Stanford University, came to CU Anschutz in 2018. It is aptly part of CU Innovations, which provides support in the translation of academic discoveries to patient benefit.
“Our faculty has the academic foundations to be wildly creative and successful,” said Kimberly Muller, managing director of CU Innovations. “But, moving early scientific discoveries from bench to bedside is quite complicated, and it requires various sets of expertise and resources. CU Innovations is working to bring those resources to the campus to surround our faculty, with the ultimate goal of getting these drugs and devices to patients as fast as possible.”
Mitchell was working on developing a medical device to help quickly implant a cardiovascular device when he learned about SPARK.
“SPARK merges a wide variety of clinicians and basic scientists with differing projects,” he said. “The program leverages the diverse experience and skill set of the fellows, promoting learning from others.”
The program is founded upon three pillars: industry mentorship, funding and training.
“The industry mentorship is really the most important piece,” said Cigdem Benam, SPARK co-director who is in charge of educational initiatives of CU Innovations. “The unique relationship built from the SPARK program helps researchers to foresee the risks in product development in early stages and work on mitigating them. It pushes them to define the end product and walk backwards in planning each step of the process with the crucial input from industry mentors.”
Beyond the mentorship, SPARK offers $100,000 in funding and educational training in innovation, product and venture development. It also attracts business leaders from all project types to campus, including venture capitalists, experts in intellectual property and other highly knowledgeable speakers.
SPARK events on campus
SPARK holds seminars every other Wednesday evening from 5 to 7 p.m. Speakers vary from intellectual property lawyers to managing partners of venture capital. While all of these educational events are available to SPARK fellows, most are also open to the public. Look for the schedule under “Upcoming Events” on the CU Innovations website as well as information on its Twitter page: https://twitter.com/cuinnovations
“Participation in SPARK has been highly rewarding,” said Mitchell. “As a novice innovator, I have the program to thank for introducing me to highly knowledgeable advisors. I have also learned many things that helped me avoid expensive and time-wasting mistakes. I would encourage anyone with a new idea or project to apply.”
The study was published today in the journal Nature Communications.
Using advanced new technology, scientists were able to identify loci or locations on a specific chromosome that may put those of African descent at a higher risk of asthma.
They also discovered four chromosomal regions usually found in whites and Asians associated with asthma. One of those chromosomal areas is known as the 17q12 – 21 region.
Despite the high incidence of asthma among those of African ancestry, it has been historically underrepresented in genome-wide association studies (GWAS) even though the African genome is the most diverse on earth.
“In the largest GWAS of asthma in African ancestry populations to date, we found strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, and we also identified two novel loci on chromosome 8 that may be specific to asthma risk in African ancestry populations,” said the study’s first author Michelle Daya, PhD, assistant professor in the division of Biomedical Informatics and Personalized Medicine at the CU School of Medicine.
According to Kathleen Barnes, PhD, the senior author on the study and director of the Colorado Center for Personalized Medicine at CU Anschutz, those of African ancestry in the Americas and elsewhere suffer a disproportionate burden of disability, disease and death from common chronic illnesses like asthma and diabetes. Yet the group has been understudied.
To better understand this population and its genetic impact, Barnes worked with the National Institutes of Health’s National Heart, Lung and Blood Institute (NHLBI) to create the `Consortium on Asthma among African-ancestry Populations in the Americas’ or CAAPA.
They sequenced the genome of 642 people of African ancestry from 15 North, Central and South American and Caribbean populations plus Yoruba-speaking individuals from Ibadan, Nigeria.
“NHLBI has been promoting basic research to understand the genetic contribution to asthma disparities across racial and ethnic groups, and the CAAPA is one of our major investments in this area,” said James Kiley, director of the Division of Lung Diseases at NHLBI and the NIH.
In this latest study, researchers looked at 7,009 asthma cases and 7,645 controls.
“From this study we can say chromosome 17q is important for the development of asthma not just in populations of European or Asian ancestry, but also those of African ancestry,” Barnes said. “This is a big step forward in untangling what is happening at this loci.”
The researchers were able to make these findings due to new technology like the development of the African Diaspora Power Chip in partnership with Illumina Inc. which allows for improved tagging and coverage of African ancestry genetic variation.
“We need to understand what is driving asthma in these populations,” Barnes said. “Now we have a much better genetic foundation for pursuing this.”
“Ultimately, we hope that a better understanding of the genetic risk factors for asthma in African ancestry populations will lead to the development of better therapeutic interventions,” she said.
Researchers from the University of Colorado Anschutz Medical Campus, in collaboration with several other institutions, have discovered a genetic defect linked to Biliary atresia (BA), the most common pediatric cause of end-stage liver disease, and the leading indication for liver transplantation in children.
Their findings were published January in the journal Hepatology.
“We don’t know the cause of Biliary atresia, which interferes with our ability to treat affected children,” said study co-author Ronald Sokol, MD, a pediatric gastroenterologist and hepatologist at Children’s Hospital Colorado and Director of the Colorado Clinical and Translational Sciences Institute (CCTSI) at CU Anschutz.
By identifying a genetic mutation linked to the disease, Sokol, along with researchers from Emory University, University of Utah, Children’s Hospital of Philadelphia, Washington University at St. Louis, and others, may finally determine the cause of this devastating condition. The group used next-generation gene sequencing to discover that a genetic defect of the gene PKD1L1 was linked to BA in a subset of patients.
Some children with BA also have splenic abnormalities and cardiac malformations called biliary atresia splenic malformation syndrome or BASM. Researchers hypothesized that the genetic factors causing an asymmetric position of organs in the body could also cause the development of BA in BASM patients, and that the genes involved could be discovered using whole exome sequencing.
So they sequenced DNA specimens from 67 subjects with BASM, including 58 patient-parent trios. Researchers looked at 2,016 genes – a subset of the full genome – that were associated with proteins that were candidates to cause a disease like BA. The study found five patients who had two copies of mutations in the gene PKD1L1 and three additional patients who had one mutation in the gene.
“The importance of this is that researchers have never identified a gene, when mutated, that causes BA,” Sokol said. “This is the first time it has been found.”
The CCTSI’s Pediatric Clinical and Translational Research Center played a key role in the study. The patients who were participants came from a liver disease research network, which Dr. Sokol chairs, the Childhood Liver Disease Research Network (ChiLDReN). This network has been funded by the NIH for 15 years and includes 14 centers across the nation, Canada and the UK.
The gene that was identified may be the first of other genes to be found to be linked with BASM or BA. Understanding what causes BA is a breakthrough that could lead to new therapeutic approaches that would ultimately avoid liver transplantation.
In the first analysis of the data, researchers looked at more than 2,000 genes. Now that they have the data from the whole exome sequencing, researchers can go back and analyze the other 18,000 genes for other genetic causes of BA.
“What we learn about what causes the disease could translate into new therapeutic targets and strategies,” Sokol said.
Guest contributor: Wendy Meyer, Colorado Clinical and Translational Sciences Institute
This past fall, CU Anschutz and CU Denver embarked on their first semi-annual policy review process which resulted in several policy updates. The Office of the Provost has announced changes to six campus administrative policies from the Academic & Faculty Affairs and General Administration areas.
All changes became effective Jan. 1, 2019, except for policy 1029 which is effective April 1, 2019.
Each policy underwent extensive stakeholder review, including faculty, staff, legal and Provost coordination as well as Chancellor’s approval. The next semi-annual policy review will take place during spring 2019.
The explosion of big data promises potential breakthroughs in disease treatments, but, just as in the development of new drugs, scientists and clinicians must exercise caution in how they apply algorithms and other technologies, according to a CU Anschutz panel of experts.
Hunter outlined examples of how machine-learning systems are used in health care. The outcomes show mixed results: while some systems delivered illuminating data that helped clinicians, other instances revealed a machine’s inability to understand the nuances involved in, for example, a basic blood draw. “The goal is not to replace doctors, but to augment them — help them do a better job and spend less time doing boring stuff and more time on doing the things that really matter to patients,” he said.
Algorithmic snake oil?
Only 100 years ago, Hunter reminded the audience, “snake oil” was often passed off as “medicine.” Just as the Food and Drug Administration (FDA) certifies new medicines as safe and effective, the same process should apply to AI, he said. “These algorithms aren’t magic … It’s really important that we treat them the same way we treat all other aspects of medicine: make sure they’re safe and effective.”
Goss, a physician in the Emergency Department, has studied how the documentation demands of electronic health records (EHR), which are intended to improve patient outcomes, can actually create problems for physicians. In one case, he said, the large amount of “free text,” or unstructured data, in a patient’s EHR resulted in a clinician missing the man’s allergy to a particular drug.
In another case, speech-recognition technology — commonly used by clinicians when dictating information into an EHR — took a doctor’s “missed-her-period” comment on a patient and translated the menstrual “period” into a simple punctuation mark. So, when the patient had a complication, her subsequent physician misread the woman’s condition and prescribed a drug that’s dangerous to pregnant women.
Developing AI tools
Goss, along with colleagues, is working to develop an AI tool that can detect errors before they are entered into the electronic record. They are also working on a standardized knowledge base of allergies and reactions, which could be applied in an easily-found fashion in the EHR.
He is also working on a universal tool to help clinicians quickly identify all information in the EHR that’s relevant to a patient’s presented condition. The goal is to ensure that clinicians can make the right care decision at the right moment.
‘Medical errors are the third-leading cause of death behind heart disease and cancer. I think artificial intelligence has tremendous potential to actually improve the safety of the care we provide our patients.’ – Foster Goss, DO
“Right now, medical errors are the third-leading cause of death behind heart disease and cancer,” Goss said. “So, I think artificial intelligence has tremendous potential to actually improve the safety of the care we provide our patients.”
Meanwhile, Smith and a large team of personalized-medicine experts are researching ways to improve therapies for acute myeloid leukemia (AML), a disease that went decades without a significant advance in treatment, and other blood disorders.
Progress was recently made on a novel new therapy, fueled by combining clinical data with new information about cancer cells, and the campus continues to make great strides in other areas of personalized medicine.
“Chancellor Don Elliman and others here have had the foresight to build such an environment, a compass where we can marry this data together, and then layer on top of it the tools that allow people to analyze the data, visualize the data, and then hopefully give us quick and accurate answers,” Smith said.
Smith noted that the marriage of data and health care knowledge is a “team sport” and requires a diverse group of experts, which exists in spades at CU Anschutz. “That’s the key for all this moving forward,” he said. “This is not an electronic-record problem, it’s not a statistics problem, it’s not a doctor problem. It’s a problem that’s only going to be addressed effectively by a big team of people who have all of these disciplines and can work well together.”
The panel answered questions from the audience, including a query on ways the campus should incorporate AI training into its health care curricula. Hunter said the curricula should be agile enough to adapt to the fast-changing technological environment. As a baseline, the curricula should educate students about the errors that may occur in AI. Beyond that, he said, the curricula could offer, for interested students, a deeper dive into the theories behind AI.
“I do think there is a baseline that ought to end up in the curriculum,” Hunter said. “We don’t have that yet.”
All of the panelists agreed that, ultimately, human capabilities and machine-based technologies must be married in complementary fashion. It’s an exciting time, they said, and the health care advancements will be for the better, but they will arrive incrementally.
“When we have these cool new technologies, we have to figure out where do they actually help in medicine?” Hunter said. “Where are the places we know we could do better, and is there a technology that could help us?”
A survey of Colorado home health care clinicians (HHCs) revealed that 60 percent said they had not received enough information to guide patient treatment while 52 percent said patients often had unrealistic expectations of the kind of care they would receive.
The study was published today in the Journal of the American Medical Directors Association.
“We have heard of medication errors occurring between hospitals and home health care providers,” said the study’s lead author Christine D. Jones, MD, MS, assistant professor at the University of Colorado School of Medicine. “As a result, patients can receive the wrong medication or the wrong dose. Some home health providers don’t get accurate information about how long to leave a urinary catheter or intravenous line in.”
Jones and her colleagues surveyed nurses and staff at 56 HHC agencies throughout Colorado. Participants were sent a 48-question survey covering communication between hospitals and HHCs, patient safety, pending tests, medication schedules, clinician contact and other areas.
More than half said hospitals did not adequately prepare patients for home health care upon discharge. They also said patients often expected a level of home care that was simply not available including extended hours, housekeeping and help with transportation.
Home health care workers with access to electronic health records (EHRs) for referring providers had fewer problems relating to a lack of information about patients, including critical medication data.
They were able to electronically access notes, orders, lab and radiology results and referrals. Some 12 percent of respondents reported positive experiences when accessing the Colorado Regional Health Information Organization (CORHIO, www.corhio.org) about hospital admissions.
Yet many did not have access to such information.
“Although almost all (96 percent) indicated that Internet-based access to a patient’s hospital record would be at least somewhat useful,” Jones said. “Fewer than half reported having access to EHRs for referring hospitals or clinics.”
She said the survey revealed problems getting medication doses right due to conflicting information.
“Notably, additional studies have found extremely high rates of medication discrepancies (94 percent – 100 percent) when referring provider and HHC medications lists are compared,” Jones said.
The study suggested targeted education of hospital staff about what home health clinicians actually provide to patients and caregivers to avoid frustration.
Jones noted that if these issues are arising in Colorado, they could signify a national problem.
“For hospitals and HHC agencies seeking strategies to improve communication, this study can provide targets for improvement,” she said. “Future interventions to improve communication between the hospital and HHC should aim to improve preparation of patients and caregivers to ensure they know what to expect from HHC and to provide access to EHR information for HHC agencies.”
The study’s co-authors include: Jacqueline Jones, PhD, RN, FAAN; Kathryn H. Bowles, PhD, RN, FAAN, FACMI; Linda Flynn, PhD, RN, FAAN; Frederick A. Masoudi, MD, MSPH; Eric A. Coleman, MD, MPH; Cari Levy, MD, PhD and Rebecca S. Boxer, MD, MS.
On Monday, researchers at the CU Anschutz Medical Campus were awarded multiple grants from the Rose Community Foundation to advance cardiology research as well as arthritis research and treatment. The one-time grantmaking is an initiative called “Heart and Soul,” awarding nearly $1.3 million to six organizations in the greater Denver area.
The grant recipients are Peter M. Buttrick, MD; Kevin Deane, MD, PhD; Judith G. Regensteiner, PhD; Jane E.B. Reusch, MD, PhD; and Josiane Broussard, PhD.
The Rose Community Foundation team members, led by president and CEO Lindy Eichenbaum Lent, surprised the researchers on campus Monday with the news.
“We are excited to support and highlight the incredible work taking place in our own backyard around cardiovascular disease and arthritis,” said Eichenbaum Lent. “These grants span the entire age continuum – supporting work that will benefit children through older adults – while also spanning the continuum of therapeutic and clinical care to trailblazing laboratory research. Our hope is that these funds will make a significant impact in the lives of Coloradans living with cardiovascular disease or arthritis – and provide transformational support to the local doctors, scientists, researchers and institutions working to improve the health of people with these conditions.”
The awards were presented to the Center for Women’s Health Research, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado:
The Center for Women’s Health Research was granted $300,000 to support the following: $200,000 for a study exploring the effects of insufficient sleep on cardiovascular fitness and insulin action, and an additional $100,000 to fund two seed grants for interdisciplinary research teams that allow for early-career researchers to gather the necessary preliminary data to obtain national funding and launch a large research project in the field.
University of Colorado, Anschutz Medical Campus was granted $185,000 to support the following: $110,000 for a new robotic workstation that expands the capacity of the arthritis research at the facility, and $75,000 for a bioinformatic and laboratory expert to identify unique heart failure signatures on over 1,300 heart tissues so that more precise treatments can be offered to patients for better outcomes.
Children’s Hospital Colorado Foundation received a $410,000 grant which includes the following: $360,000 to fund a two-year study to identify compounds that improve heart function in children with heart failure and test whether physical exercise improves heart function in children with heart failure, and an additional $50,000 to purchase software for an ultrasound machine that improves treatment for pediatric rheumatoid diseases by allowing for clearer imaging and more targeted joint treatment in children, and laboratory equipment to further accelerate care and research for a cure.
“These philanthropic gifts from the Rose Community Foundation’s “Heart & Soul” initiative will accelerate vital work at the University of Colorado Anschutz Medical Campus, and we are proud to partner with such a visionary and committed leader in our community to transform health care,” said John J. Reilly, Jr., MD, CU School of Medicine dean and vice chancellor for health affairs. “This generous support will speed innovative research in cardiology and fund essential equipment for arthritis research and treatment, ultimately helping our talented physician-researchers improve care and quality of life for countless patients.”
Amy Bohrer, office supervisor in the Department of Surgery, CU School of Medicine, recently received the U.S. Navy Bureau of Medicine and Surgery’s Reserve Duty Sailor of the Year award. Bohrer will go on to represent Navy Medicine in the Commander, Navy Reserve Force Sailor of the Year competition.
Navy Medicine consists of more than 30,000 active duty and reserve hospital corpsmen that deploy with Sailors and Marines worldwide, in both wartime and peacetime. The rating is the largest, most professionally diverse and highly decorated enlisted corps in the Navy.
Navy Medicine is a worldwide health care network of 63,00 personnel that provide health care support to the U.S. Navy, Marine Corps, their families and veterans across the globe.