Bond LSC scientist delves into how domestication alters the fox brainRussian silver foxes that have been tamed show changes in their brains. | photo provided by Anna Kukekova
By Roger Meissen | Bond Life Sciences Center
You might be familiar with the idiom “don’t bite the hand that feeds you,” but when it comes to a certain lineage of tame Russian silver foxes it’s quite literal.
After more than 50 generations of breeding, these tame foxes likely offer insight into how selective breeding leads to domestication, and scientists dove deeper to look at what this trait might mean in terms of changes in the brain and the genes behind them.
“These silver foxes act like domesticated dogs and are assumingly a good model to look at the process of domestication, tracing what happened as the wolves became domesticated into what we recognize today as the domesticated dog. Wouldn’t that be fascinating to know all the things that coincide with that?” said Cheryl Rosenfeld, a Bond Life Sciences Center principal investigator at the University of Missouri and co-lead author on the study. “Presumably, to become domesticated the one biggest organ that would have to change is the brain, because that’s where fearfulness, aggression, and social behaviors emerge from, so my interest is in the brain and how various factors might affect it.”
The path away from aggression
While this story eventually focuses on the brain, the path to a modern model of tameness starts in Soviet Russia in the 1950s.
Russian geneticist Dmitry K. Belyaev bred hundreds of foxes in Siberia, initially selecting them based on their willingness to approach humans in their cage. In its beginning only 10 percent of those tested showed a weakened wild response, and those foxes were bred together to reinforce this docile nature. In later generations, their behavior was further evaluated based on their likelihood to interact with humans approaching their cage, their territorial behavior, response to attempts to pet them and reaction to the experimenter leaving the interaction. Lyudmila Trut, his intern now in her 80s and an author on this study, continues the breeding project.
“Those that showed a muted wild response would get bred together, so with each passing generation, the foxes showed diminished fear response. Once they established this tame fox population, they eventually developed the aggressive ones doing just the opposite in that they paired those foxes showing the most aggressive responses to an experimenter approaching the cage,” Rosenfeld said. “They repeated this over time and, ultimately, what they have now, going out 50 generations, are tame foxes that act and even look in some ways like pet dogs.”
The tame silver foxes love human interaction from attention to belly rubs, and exhibit traits like tail wagging, gazing into the faces of humans and a change in their barks. Physical changes accompanied these behavioral changes, with coat color shifting from silvered-black fur to a more mottled, piebald pattern, and tails becoming curly despite these traits not being intentional selected for by breeders. In contrast, those bred for aggression showed hyper aggressive responses to humans, as indicated by lunging at the cage.
The taming of the brain
A change in behavior as observed in these silver foxes likely comes with unseen shifts in genetics and brain function. Rosenfeld decided to look at these changes in the hypothalamus region of the brain with the help of researchers from the University of Illinois at Urbana-Champaign, Cornell University, the Broad Institute of MIT and Harvard and the Institute of Cytology and Genetics in Novosibirsk, Russia.
“We are interested in changes in gene expression associated with the hypothalamic-pituitary-adrenal axis, the main hormonal system involved in stress-response and it was very exciting and productive to collaborate with Dr. Rosenfeld and her colleagues on the analysis of gene expression in the hypothalamus of tame and aggressive foxes” said Anna Kukekova, the senior author and associate professor in the Department of Animal Sciences at the University of Illinois at Urbana-Champaign.
Rosenfeld compared genes in the hypothalamus between tame foxes and aggressive foxes as well as comparing them to genes in two other brain regions — the prefrontal cortex and the basal forebrain — significant in terms of learning and memory.
“The hypothalamus was a good target organ, because it controls social behaviors like getting along or gregariousness and usually hormones like the pro-social hormone oxytocin tends to increase in animals who are social,” Rosenfeld said. “We basically did a global approach, looking at every gene we could identify and how they differ in terms of expression between the tame and aggressive foxes.”
Among genes with differential hypothalamic expression in tame and aggressive foxes they found seven identical genes with the same pattern of expression between all three brain regions. It suggests that when you select for tameness that some genes will change regardless of brain region.
“It was interesting to us because these genes were involved in processes including cell division and making more neurons, differentiation, adhesion like how the cells contact each other, and the most surprising, carbohydrate processing.”
Rosenfeld commented that some of these involved — such as, carbohydrate processing — suggest potential changes to accommodate domestication between the tame and aggressive foxes. This falls in line with how scientists believe dogs became domesticated 10,000 years ago, growing ever closer to human populations and developing to scavenge their scraps and garbage, although in this study both tame and aggressive foxes were maintained on the same diet.
“As animals get domesticated, they have to also accommodate different diets than what they’ve been eating in the wild because now they’re getting scraps from humans,” Rosenfeld said. “They’re selecting for genes that are involved in carbohydrate process, like metabolism processing, so it’s sort of telling us when you consider domestication that we might have to think about how the animal may have to then turn on a whole set of other genes to accommodate this new diet.”
But there were other brain differences as well.
“We also found genes suppressed in tame foxes associated in inflammation processes we call interleukin signaling, cytokines production and communication between cells to each other, and this gene expression linked to whether they were tame versus aggressive.”
The researchers’ original idea that genes related to hormones like oxytocin ended up not panning out when they saw little change between tame and aggressive foxes. But, she said it was interesting that the prevalent changes they did see involved more genes down-regulated or suppressed in tame than aggressive foxes.
“Most of the genes in the hypothalamus actually we found were suppressed in tame relative to hyper aggressive foxes, you know, squashing a hyperactive response, Rosenfeld said. “So, it’s an interesting question to consider that, as dogs became more domesticated, did they become more prone to disease because they don’t have such a heightened immune response? We can’t really answer that question just yet.”
Kristal Gant, a former MU PREP Scholar and current Ph.D. candidate at the University of Wisconsin – Madison | photo by Roger Meissen, Bond LSC
By Roger Meissen | Bond LSC
Kristal Gant is a long way from the student she was when she donned a lab coat and wielded a pipette in labs at Bond Life Sciences Center nearly four years ago.
As she stood in front of a group of MU students hoping to one day follow their own routes to graduate school, Gant recounted her long and winding path to her Ph.D. program at University of Wisconsin-Madison and how MU’s Post-Baccalaureate Research Education Program (PREP) Scholars helped her get there.
“I’m really passionate about wanting to give back and be kind of like a mentor, but also a motivational, navigational tool for these students,” Gant said. “In undergrad, I didn’t have any idea about research and I feel like it’s my duty to come back and talk about my experience. Most of these students have not seen people that look like them in graduate school, as Ph.D. candidates or doctors. They don’t even know that’s possible for themselves.”
Gant didn’t attend Mizzou for her undergraduate degree, but as a PREP Scholar here she gained the chance to hone her skills. It gives underrepresented groups opportunities for individual academic and professional development that range from mentoring and GRE preparation to mini courses and research experience. The end goal is to prepare them for applying to Ph.D. programs. Those in PREP spend one or two years refining their skills and knowledge.
Gant greatly expanded her experience in research during that time. She spent a year alternating between the labs of Cheryl Rosenfeld and Mike Roberts in Bond LSC, learning the ins and outs of research on reproduction and environmental chemicals like bisphenol A (BPA).
“It gave me a preview of what you go through in your first year of grad school. I knew I wanted to study reproduction, reproductive deficiency and disease, and was also interested in environmental and reproductive toxicology, initially,” Gant said. “When I came here, I had the best of both worlds; I had the BPA aspect with Dr. Rosenfeld looking at mouse models and how that affected their behaviors and I had the reproduction area where Dr. Roberts looks at placental development by converting embryonic stem cells to trophoblasts, the main cells responsible for placental function. The project was essentially perfect in accommodating both of my interests.”
Gant had a unique, sometimes turbulent path to her interest in science. She grew up and went to school on the Westbank of New Orleans, until ninth grade. She remembers first getting an interest in science in junior high when her teacher showed a time-lapse video about pregnancy and the development of a baby.
“I was really interested in like how the woman’s body knew to accommodate the baby and how it adapted to having another human inside of it. That really intrigued me, so I was like, ‘I want to do reproduction,’” Gant said. “That combined with “The Cosby Show” made me want to be a neonatal nurse or obstetrician. I pursued that initially, but then I was like, oh, whoa, I didn’t know you could actually research these things, and I was introduced to research careers and grad school in college and realized this could be a thing. So, yeah, I’m a nerd like that.”
Before she got there, life got a little derailed. When Hurricane Katrina hit, the 15-year-old girl got separated from her mother who was visiting her sister in Virginia, causing her to have to relocate to Texas with a family friend to avoid the storm. What started out as a few days of inconvenience quickly turned into a bigger situation.
“We saw on the news that there was extensive flooding and people were stuck on the roads, and our apartment was flooded out, so we lost everything,” Gant said. “My mom didn’t know if I had made it out or anything because the phone lines were down and we were separated two weeks before the family I was staying with in Texas flew me to Virginia where I ended up finishing high school.”
Gant completed a year of college at Virginia Commonwealth University before she moved to North Carolina to help her mother escape a domestic violence situation. They were left living in a shelter for abused women and children for a year before getting their own apartment, and Gant worked at McDonalds until she started college again at Elizabeth City State University. She graduated in 2014 and followed up with a couple internships before ending up in a customer service job.
“And I hated it because it was, like, I have a whole degree that I’m doing nothing with and I’m in debt from it and I need to do something with,” she said.
A former adviser recommended Gant apply for PREP Scholars to improve her chances of getting into grad school.
Kristal Gant talks with students eager to gain insight into applying to Ph.D. programs at Bond LSC in fall 2019. | photo by Roger Meissen, Bond LSC
Gant said her struggles helped her figure out what she wanted to do and shaped how she saw her future. Understanding it also aided her in writing personal statements for graduate school applications. She related that insight to those current PREP students looking to her for advice.
“It requires a lot of self-reflection to understand how your struggle got you to where you are. It doesn’t have to be family or a natural disaster or relationship troubles or whatever. It could be something within you that you yourself struggle with internally, whether it be confidence or fear or a feeling of not being good enough to do something,” Gant said. “It could be something so small that you struggled with, overcame and still, you pursued something you were deathly afraid to do. That shows that no matter what is supposed to stop you, you’re not gonna allow it.”
But her parting advice was some of the best.
“It really takes a passion, knowing what you’re trying to answer and putting in the work to figure it out. If you’re not passionate then you will be miserable and feel like you’re trapped in a prison,” she said. “But if you want the answers to your research questions and will not rest until you figure it out, then you should be in graduate school.”
Kristal Gant is a fourth-year Ph.D. candidate at the University of Wisconsin-Madison studying Endocrinology and Reproductive Physiology in the Department of Obstetrics and Gynecology. She was an MU PREP Scholar in 2015 and plans to graduate with her doctorate in 2021.
Saurav Sarma grew up amongst tea plantations and medicinal plants in the northeastern corner of India near Tibet, a state called Assam.
His day-to-day observations of the plants sparked a curiosity that eventually led him to a career looking at the chemical building blocks behind it all in the labs of Lloyd Sumner and the University of Missouri Metabolomics Center at Bond Life Sciences Center.
His interest revolved around the connections between carbon, oxygen, nitrogen and hydrogen, which make up living systems.
“How they’re connected makes all the difference,” he said.
Sarma enjoys working in the metabolomics core because of the incredible facilities and collaboration. Among other things, his job is to look for thousands of molecules to find biomarkers for various diseases.
“The purpose of the core is to profile the small molecules,” he said. “So, for example, a group might want to see the molecular differences between a healthy plant and a diseased one. There are thousands of molecules, so you need sophisticated techniques to profile those molecules because they are otherwise unknown.”
Sarma works with people on and off campus who are curious about the molecules in their areas of research, but he also does data analysis, communication and collaborative research project. He enjoys the diversity of his job, which is focused on how molecules shape our lives.
“Finding something new is always exciting,” he said. “Science can always surprise you.”
While he finds this research to be fascinating, he also enjoys how it can help people and push civilization forward. From health to the economy to agriculture, he said science benefits us in ways we often don’t realize or think about.
“So, it’s not that my work is great, it’s that everybody’s work is great,” he said. “Everything that we use nowadays didn’t come up in one day, it’s from people’s hard work over many years, and maybe someone will benefit from our work in the future.”
Things may not always go as planned, but he doesn’t let that stop him.
“In science, nothing is a failure,” he said. “The knowledge you are generating today is helping researchers in the future, so learning how to deal with failure and keeping an open-mind is important.”
He said that it’s easy to get stuck in mental patterns, and by keeping an open-mind, you’re more likely to see or think of things you might not otherwise see in your own research, in conversations and daily life, too. Many of the most important discoveries of humanity occurred outside of the normal paradigm. And while ‘failure’ can be challenging and frustrating, he said it makes the success more significant.
“As a synthetic chemist, I run a hundred reactions and maybe 10 work and 90 fail,” he said. “So, it helps you to deal with failures, but it also feels great when you reach a goal. You are getting through hurdles and it gives you this satisfaction of getting something done that wasn’t easy to get done.”
He received his undergraduate degree in science, followed by a masters in organic chemistry before making the journey to North Carolina for his Ph.D. in medicinal organic chemistry. After his Ph.D., he arrived at MU in the radiology department for his postdoc. While there, he developed a trimodal drug delivery system called closomer to help minimize the side effects of cancer.
“I was fascinated by working with drug delivery systems, but then again, it was about molecules and their characterization and identification,” he said. “That’s been a binding thing throughout all of my research.”
Apart from science, he loves the classics – literature, music, sports and movies. He’s currently reading “Thousand Splendid Suns.” He also loves hanging out with his four-year-old daughter watching cartoons. “I don’t have any exceptional hobbies,” he said.
A personal career goal of his is to develop sophisticated methods for exploring more of the chemical space that is still unknown, and he hopes to see a greater breakthrough for cancer treatment in his lifetime that allows for less pain and side effects.
Amanda Paz Herrera extends her passion for research to teaching others when teaching science. | photo by Roger Meissen, Bond LSC
By Mariah Cox | Bond LSC
Dry erase markers and Styrofoam molecular models are a part of Amanda Paz Herrera’s repertoire when teaching complex scientific processes to the average person.
Teaching the next generation of scientists requires work and discipline, but Paz Herrera is up for the task.
Paz Herrera takes her science on the road with Science on Wheels, a traveling group of graduate students and postdoctoral researchers at MU who aim to make science accessible to rural communities in Columbia’s surrounding counties. Sciences on Wheels visits schools, nursing homes, clubs and public events making it imperative to communicate complex scientific processes and mechanisms to all learning levels.
“We should be able to build a knowledge bridge to communicate what we as scientists do without jargon making people feel uncomfortable,” said Paz Herrera, a third-year biochemistry Ph.D. student in Donald Burke’s lab at Bond LSC. “We’re supported by taxpayer money, so the community has a right to know how that money is being used and how we’re moving forward scientifically.”
Paz Herrera emphasizes the importance of diversity and representation in the field on top of her passion for science education and outreach.
“Scientists look like you and me and there’s way more diversity than is depicted in popular thought,” Paz Herrera said. “One of the reasons I do science on wheels is to show what a scientist can look like and that brings a lot of power to little kids that may look like me. When they see someone that looks like them that can do this, that is life-changing.”
Paz Herrera’s research has been driven by her desire to see and understand things at the tiniest level. When she was in the second grade, she owned a play light microscope and would look at her hair or the fibers from her shirt.
When going through the three rotations at the start of her doctorate program, Paz Herrera visited a nuclear magnetic resonance lab and an X-ray crystallography lab, both of which would provide her expertise in studying biology at the structural level. However, her third rotation in the Burke lab changed her perception of what the rest of her program could look like.
While the Burke lab doesn’t specialize in structural biology, its focus on viruses and cancers offers an avenue for Paz Herrera to apply her interest.
A recent study Paz Herrera collaborated on with her colleagues from the Burke lab and researchers across campus optimized RNA and DNA molecules, called aptamers, to carry cancer diagnostics or therapeutics like backpacks to receptors on cell surfaces.
Now, Paz Herrera is looking to visualize the interaction of those same molecules with a protein on the cell surface of the Ebola virus for her dissertation.
However, working with the actual Ebola virus requires a biosafety level 4, and the Bond Life Sciences Center only has a biosafety level 2. So, the researchers in the Burke lab had to get creative.
To study the virus interaction in a safe manner, collaborative researcher Alex Bukreyev who works in Galveston, Texas, engineered a lab model that combines a cattle virus with the protein present on the Ebola virus cells. Because the virus only infects cattle, researchers won’t be infected but can still study what they’re most interested in – the glycoprotein on Ebola cells.
Paz Herrera wants to visualize the interaction to understand how that happens. Understanding the interaction between the proteins on the surface of cells and the aptamers can help researchers develop drugs or diagnostics further down the line.
Visualizing it isn’t as easy as looking under a microscope. By themselves, aptamers can’t be seen on the surface of a cell, making it impossible to find where they are or see how they are functioning.
Paz Herrera is working on building a ‘plug-and-play’ modular dart made up of an aptamer, an interjecting body and a gold nanoparticle tail. The gold nanoparticle tail allows her to see where the aptamer is and subsequently visualize the interaction happening.
Amanda Paz Herrera displays her gold nanoparticle models which accompany her at science outreach events. | Photo contributed by Amanda Paz Herrera
Using a basic electron microscope available in Mizzou’s Electron Microscope Core, Paz Herrera has begun to infer where the interaction is using staining. However, she is looking forward to using cryo-electron microscopy (CryoEM) that will soon be available. Using CryoEM will allow her to see the aptamer interaction embedded in ice, providing more molecular detail.
The interjecting body in her model joins the gold nanoparticle with a compatible aptamer. This technology can expand far past Ebola and will help researchers study the interaction between aptamers and proteins in other applications.
Paz Herrera didn’t have much research experience as an undergrad. Instead, she did a lot of educational outreach with elementary and high school students.
“I would do cheek cell samples with them. They would swab the inside of their cheek, put it on a slide and stain it and see their own cells,” Paz Herrera said. “They would go crazy.”
As she progressed in her biochemistry career, she learned that there was more to science than viewing cells under a microscope. She saw graduate school as an opportunity to solidify herself as a scientist and also to prepare to teach the next generation of scientists.
“I really want to do what some of the best professors did for me – to inspire a thirst for inquiry and asking questions,” Paz Herrera said. “When a professor uses an acronym in class, they expect you to understand what they’re saying, but learning isn’t like that and shouldn’t be like that. Sometimes we have great experts in the field that have the curse of knowledge and don’t have the best tools to communicate that knowledge.”
Paz Herrera is also minoring in college teaching and has been shadowing Margaret Lange’s classes, an assistant professor in the Department of Molecular Microbiology and Immunology, to prepare herself as a future educator. She also has the ambitious goal of being a guest lecturer in all of the biochemistry undergraduate classes to strengthen her skills and receive feedback.
Her goal is to make learning science more relatable and enjoyable.
“As I progress in my education, although I become focused in my field, I will never forget where I started so that when I teach, I can break the complexity barrier,” Paz Herrera said. “I want to make science appealing, understandable and accessible not only to my future students but to the community and public as well.”
Missouri Life Sciences Week 2019 has come to a close. It brought us a taste of science across our broad research community at Mizzou. From students presenting their hard work in labs to core facilities showing what they do to advance the work of scientists across campus, Bond LSC was bustling with energy.
If you missed the action, get a taste of what it all in the photos from the week’s events below or our daily recap email links below.
But first, here’s a list of winners from the research poster session contests. It’s a challenge to pick the best research presentations from a field of nearly 300 posters. With the help of a small army of volunteer faculty and postdoctoral students, organizers narrowed the field to 39 undergrad and graduate students who skillfully explained quality science created through their research.
Winners
Social & Behavioral Sciences 1st: Hadeel AlQadi “An Overview of Cognitive Diagnosis Model for Dichotomous Latent Variables.”
Adviser: Sangbeak Ye2nd (tie): Kelsey Irvin “Sensitivity of the Reward Positivity Event-Related Potential to a Savoring Affect Regulation Strategy.”
Adviser: Debora Bell2nd (tie): Kolter Grigsby “The Role of Nucleus Accumbens CREB and PKIα modulation in Rescuing Low Voluntary Running Behavior.”
Adviser: Frank BoothLife Sciences Innovations
1st: Faye McGechie “Using Novel 3D Techniques to Visualize and Quantify Primate Neck Anatomy.”
Adviser: Carol Ward
2nd (tie): Aditi Mishra “Generation Of Novel Thermogenetic Tools In Drosophila Melanogaster.”
Adviser: Troy Zars
2nd (tie): Li Lee “T2-mapping Magnetic Resonance Imaging As A Novel Strategy To Detect And Quantify Myocardial Fibrosis In Mice”
Adviser: lixin Ma
Honorable Mention: Chunye Zhang “The Influence Of Gm Richness And Transfer Method On Disease Susceptibility In An Animal Model.”
Adviser: Aaron C. Ericsson
Honorable Mention: Paige Gruenke “2′-Fluoro-Pyrimidine-Modified RNAs Strongly Inhibit HIV Reverse Transcriptase.”
Adviser: Donald Burke-Agüero
Animal Biology, Health and Disease 1st: Karl Kerns “Sperm Capacitation-induced Zinc Efflux is Necessary for Increased Proteasomal Activity and Release from Oviduct Glycans of the Sperm Reservoir.”
Adviser: Peter Sutovsky
2nd: Alexis Dadelahi “B Cells Inhibit CD4-mediated Protection During Brucella Melitensis Infection via an MHCII-dependent Mechanism.”
Adviser: Jerod Skyberg
3rd (tie): Emma Stephenson “Effects of Copper, Zinc, and Manganese Source and Concentration during Late Gestation on Fetal Growth and Mineral Status of Calves.”
Adviser: Allison Meyer
3rd (tie): Monica Witzke “Experimental Heat Stress Alters the Fecal Microbiome of Dairy Cattle.”
Adviser: Pamela Adkins
Honorable Mention: David Korasick “Investigating the Dynamic and Complex Oligomeric States of Aldehyde Dehydrogenase 7A1.”
Adviser: Jack Tanner
Honorable Mention: Kinjal Majumder “Parvovirus Minute Virus of Mice Interacts with Sites of Cellular DNA Damage to Establish and Amplify its Lytic Infection.”
Adviser: David Pintel
Plant Biology, Health and Disease 1st: Jan Lorie Robil
“The Role of Auxin in Vein Patterning in Maize Leaves.”
Adviser: Paula McSteen
2nd: Jared Ellingsen “Establishing the Roles and Interactions of E3L1 and MKP1 in Pattern-triggered Immunity.”
Adviser: Scott Peck
3rd: Caio Canella Vieira “Major Gene for Resistance to Root-knot Nematode Sustains Yield Response Under High Nematode Pressure.”
Adviser: Pengyin Chen
Comparative and Translational Medicine
1st: Kari Chesney “Modeling Crohn’s Disease: Identifying Environmental Triggers in a Genetically Susceptible Atg16l1 Rat Strain.”
Adviser: Elizabeth Bryda
2nd: Robert Kazmierczak “Targeting Neuroendocrine Prostate Cancer.”
Adviser: Chiswili Chabu
3rd: Lindsey Ledbetter “Eosinophils Are Important for Early Formalin-inactivated Coxiella Burnetii Phase I Vaccine-mediated Protection and Antibody Isotype Switching.”
Adviser: Guoquan Zhang
Honorable Mention: Catherine Chambers “IL-1 is Protective in a Murine Model of Neonatal Meningitis-Associated E. coli Infection.”
Adviser: Jerod Skyberg
Honorable Mention: Hien Huynh “Antigen Requirements to Achieve T Cell Co-potentiation When Targeting Human CD3 with Fab Fragments in Humanized Mouse Models Expressing Transgenic TCRs.”
Adviser: Diana Gil Pages
Honorable Mention: Sessaly Reich “HER2 Antibody Validation in Dogs and Expression Pattern in Canine Osteosarcoma Cell Lines and Tissues.”
Adviser: Jeffrey Bryan
Ecological and Evolutionary Biology
1st: Makenzie Mabry “Brassica oleracea: The Dog of the Plant World.”
Adviser: J. Chris Pires
2nd: Troy Rowan “Detecting Signatures of Selection and Local Adaptation in United States Bos Taurus Beef Cattle.”
Adviser: Jared Decker
3rd: Erin Petty “Which Resources Control Algal Biomass in Turbid Missouri Reservoirs: Light or Nutrients?”
Adviser: Rebecca North
Honorable Mention: Micah Turrell “Evaluating the Critical Thermal Maxima Among Four Species of Missouri Salamanders.”
Adviser: Manuel Leal
Bioinformatics and Computational Biology
1st (tie): Sadia Akter “A Machine Learning Approach for the Prediction of Endometriosis Using Multi-OMICS Next Generation Sequencing Data.”
Adviser: Trupti Joshi
1st (tie): Nicholas Mattia Marazzi “Quantitative Evidence of the Role of the Lymphatic System in Maintaining the Subatmospheric Pressure Condition in the Interstitial Space.”
Adviser: Giovanna Guidoboni
3rd: Adil Al-Azzawi “Super Clustering Approach for Fully Automated Single Particle Picking in Cryo-EM.”
Adviser: Jianlin Cheng
Undergraduates
1st: Olivia Botonis “Distinct Roles of Two Dopaminergic Pathways in Reinforcement Learning.”
Adviser: Ilker Ozden
1st: Andrew Yowell “An Essential Endopeptidase is Required for Cell Wall Synthesis and Morphology in A. tumefaciens.”
Adviser: Pamela Brown
2nd: Maha Hamed “Role of Salicylic Acid in Immune Responses in Arabidopsis Clathrin-Coated Vesicle Mutants.”
Adviser: Antje Heese
2nd: Alec Wilken “Functional Morphology of the Palate in Varanus exanthematicus and Its Significance for the Evolution of Cranial Kinesis.”
Adviser: Casey Holliday
3rd: Mason Ward “Say Yes to the Host: The Effects of Drought on Parasitoid Wasp Behavior.”
Adviser: Debbie Finke
Honorable Mention: Aleks Shin “Quantitative Analysis of Glycated Albumin by LC-MS/MS Using an Isotopically Labelled Standard.”
Adviser: Kuanysh Kabytaev
Honorable Mention: Skyler Kramer “Novel Improvements on a Machine Learning-based Approach for Large-scale Prediction of Negative-mode Collisional Cross Sections.” Adviser: Lloyd Sumner
Honorable Mention: Kody Jones “Uncoupling Functions of Dynamin-related Protein Network in Plant Immune Responses from Development.”
Adviser: Antje Heese
Lead Organizer for Each Category
Social & Behavioral Sciences, Nate Green
Life Science Innovations, Mike Lewis
Animal Biology, Health and Disease, Jim Amos-Langraf
Plant Biology, Health and Disease, Scott Peck
Comparative and Translational Medicine, Jeff Bryan
Ecological and Evolutionary Biology, Rex Cocroft
Bioinformatics and Computational Biology, Chi-Ren Shyu
Undergraduates: D Cornelison
Alexandra Diller Costello explains her research poster Monday morning during the Missouri Life Sciences Week 2019 poster session. | photo by Roger Meissen, Bond LSC
Aishik Das explains his research on optical film and coating properties in Poster Session I during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Anmol Sethi points out images of the 3-D reconstruction of a gecko skull on her research poster in Poster Session I during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Reprensentatives from Truman VA Hospital talk to those browsing the Facilities and Core Exhibit Show Monday, April 15, at Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Robb Krumlauf gives a talk on regulating the balance between pluripotency and differentiation in development, disease and evolution in Monday, April 15 in Monsanto Auditorium during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Daniel Davis (Assistant Director of the Animal Modeling Core), teaches about CRISPR/CAS9 genome editing in a workshop Tuesday, April 16 during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Zahra Nourian (center), asks instructor Daniel Davis questions after a workshop on CRISPR/CAS9 genome editing in a workshop Tuesday, April 16 during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Laura Page, director of Professional Development & Leadership at the MU Graduate School, leads a talk on individual development plans during the Framing Your Future Career Conference for Graduate Students and Postdoctoral Fellows on Tuesday, April 16, during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Bryce Page, an MU grad student in biochemistry, talks with a representative from eurofins at the networking career fair of Framing Your Future Career Conference for Graduate Students and Postdoctoral Fellows on Tuesday, April 16, during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Victoria Bence and David Railton check in poster session presenters April 17 in front of Monsanto Auditorium during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Catherine Gjerstad presents an undergrad research poster in Poster Session II during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Austin Kimes presents an undergrad research poster in Poster Session II during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Sean Pirrone presents an undergrad research poster in Poster Session II during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Saivaroon Gajagowni presents an undergrad research poster in Poster Session II during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Stephanie Scott presents an undergrad research poster in Poster Session II during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
Elizabeth Bryda gives a workshop on “How to be a Genotyping Pro” April 17 during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
The audience listens as Clarissa Henry discusses results that showed the impact of the flu virus on muscle fibers in model zebrafish during her lecture April 17 in Monsanto Auditorium during Missouri Life Sciences Week 2019 at Bond LSC. | photo by Roger Meissen
The MU community browses companies at the Vendor Expo Thursday, April 18, in MCQuinn Atrium during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
The MU community browses companies at the Vendor Expo Thursday, April 18, in MCQuinn Atrium during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Dr. Daisy YuanYuan Shen explains her analysis of immunogenomic pathways and survival rates in breast cancer at the third poster session Thursday, April 18, in Bond LSC during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Murugesan Raju talks about lung cancer biomarkers and translational precision medicine at the third poster session Thursday, April 18, in Bond LSC during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Alessandra Cecchini-Porciani talks to Donald Burke about the role of EphA7 in differentiation of skeletal muscle precursors at the third poster session Thursday, April 18, in Bond LSC during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Beronda Montgomery, an MSU Foundation Professor of Biochemistry & Molecular Biology and Microbiology & Molecular Genetics at Michigan State University, melded plant science research with mentorship in her talk Thursday, April 18, in Monsanto Auditorium for Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
Students joined a conversation with Beronda Montgomery on how to be a good mentee Thursday, April 18, in Bond LSC during Missouri Life Sciences Week 2019. | photo by Roger Meissen, Bond LSC
With eyes wide open, glued to metal tubes, researchers from across the University of Missouri’s campus are searching for answers that are unseeable to the unequipped human eye.
The Advanced Light Microscopy Core is a resource for anyone to come and further understand their research. The Core’s Imaging Specialist, Frank Baker, has been an intermediary between the facilities equipment and researchers for four years.
Molecular cytology is the localization of molecules within the cell. In other words, researchers look at molecular methods occurring to understand cellular functions. The core has a number of resources such as confocal, super-resolution and digital light-sheet microscopes.
Though microscopes are normally thought of as a scope to look directly into, new technology is available that can create 3D images on a monitor of the cells.
Baker points at the 3D image of an individual cell. In this case, the colors are stained to show the cell wall. Researchers can manipulate the image to analyze certain aspects of a cell. | photo by Danielle Pycior, Bond LSC
“One thing I like about working here is it gives me a perspective about the diversity of work being done at the university,” Baker said.
For Baker, one of the greatest parts about MU is its interdisciplinary nature. Any researcher from any department can bring their goals and their problems to the MCC and search for answers, and Baker gets to be a part of that journey.
“And sometimes when the problem is especially confounding, and you have all of these pieces that don’t make sense, you have that mental flash when everything integrates together into an answer. It’s a really beautiful moment,” Baker said.
Baker began his science journey here at MU where he received his undergraduate degree. He then moved on to Berkley to study plant developmental genetics and then did his postdoc at Pennsylvania State.
“I’ve always liked microscopy quite a bit, even in my undergrad days,” Baker said. “I thought, I really do like doing this, and so I decided to make a transfer.”
Baker looks through a microscope at a cell culture that is used to train researchers who come in to use the equipment. | photo by Danielle Pycior, Bond LSC
Baker has been in the MCC for four years now and said he is content for the moment.
“It’s always interesting because people come with new problems and new types of experiments, and so with the job, there is always a goal to keep learning,” Baker said.
On the horizon, Baker can see a future where he directs his own core. He said it’s important to him that it stays fairly broad to serve multiple purposes, similar to the MCC. Baker believes in setting goals and collaborating with others to reach them.
“I enjoy this job for a number of reasons. I like the diversity of work being done here… it does provide a sense of mission. Because the work that is being done here is critical to a lot of work being done at the university,” Baker said. “I enjoy that sense of working to achieve both the universities goal to support researchers and also to see work happen that has a positive effect.”
While goals can vary is size and scope, Baker makes it a priority to see both the small and big picture. When he can’t understand something about his research, he finds it useful to step back and take a look at the larger community, or to look at previous work being done on the topic. He values the complexity of science and how a change in perspective can be a shift in understanding.
“What I love about science is looking into the unknown, not knowing what the answer is, devising a hypothesis based on what you do know, and then doing the experiments to find out what the answer is,” Baker said.
Male Amami spiny rats have the rare distinction of not having a Y chromosome. Scientists at MU’s Bond Life Sciences Center are trying to decipher how exactly their sex is determined during development. | photo by Asato Kuroiwa, Hokkaido University
By Roger Meissen | Bond LSC
Joint press release by University of Missouri and Hokkaido University
What causes rats without a Y chromosome to become male?
A look at the brains of an endangered spiny rat off the coast of Japan by University of Missouri (MU) Bond Life Sciences Center scientist Cheryl Rosenfeld could illuminate the subtle genetic influences that stimulate a mammal’s cells to develop as male versus female in the absence of a Y chromosome.
The root of the answer is in the chromosomes of this particular mammal. Males of the Amami spiny rat (Tokudaia osimensis) are not like most therian mammals — a name used to group animals that give live birth including placental mammals and marsupials. Unlike in most mammals, these males have no Y chromosome, which has been shed over eons of evolution. And they only have one X chromosome.
“I’d been interested in these rats for many years now, and it’s unclear how sexual differentiation of the gonads and brain occur in this species since both males and females have a single X chromosome,” said Cheryl Rosenfeld, lead author on the study and an MU researcher.
Since most mammals inherit chromosomes from both parents — an X from our mother and either an X or Y chromosome from our father — the only way to develop as male is to inherit a Y chromosome. That male chromosome contains a sex-determining region Y (SRY) gene that stimulates male sexual differentiation in many mammalian species, including humans. SRY triggers the fetus to become male by producing a protein that binds DNA, which leads to development of testes and subsequent production of testosterone. This steroid hormone then stimulates development of the rest of the male reproductive tract. This surge in testosterone from the testes also programs masculinization of the brain.
Naturally, this got Rosenfeld curious about how the absence of a Y chromosome and SRY might affect gene expression differences in male and female Amami spiny rats. In collaboration with Asato Kuroiwa from Hokkaido University Takamichi Jogahara of the Frontier Science Research Center in Japan, and Scott Givan, associate director of the MU Informatics Research Core Facility, her laboratory received brain samples from both males and females of this species.
They took those brains, isolated the RNA from them and sequenced the samples of the male and females to compare transcripts between the two sexes. Transcripts are the step between a gene and a protein, essentially a piece of RNA that encodes the information to make a particular protein. Subtle variations in the resulting RNA can change the final protein, giving rise to alternative forms that can exhibit increased or decreased potency. Investigators found major differences between males and females.
“Several different transcripts or isoforms encode the same gene, and while there might be, for example, 10 transcripts for a particular gene, some transcripts are more potent than others and have more effect in individual cells,” Rosenfeld said. “When we compared males to females, there were several hundred more transcripts upregulated in males than females. Our thought is that since both have the same sex chromosomes, the resulting differences could be originating from the fact that the males might have more of one of the more potent transcripts.”
Expression differences in such transcripts might also arise due to epigenetic changes, which are alterations that affect the turning on/off of certain DNA regions but without affecting the DNA itself. Potentially, in females, these more effective transcripts are not expressed because of such epigenetic changes.
When the team – including MU student Madison Ortega who is in the MU Maximizing Access to Research Careers/Initiative for Maximizing Student Diversity (MARC/IMSD) program — looked closer, they realized many of the transcripts expressed in males encode for various zinc finger protein genes. In males, these genes can be turned on by SRY and are thought to significantly influence sex development.
“What we think might be happening is the males might be turning on all these other zinc finger transcripts that may compensate for the absence of SRY, so they influence undifferentiated gonad to become a testes and help program the brain to be male. Without these zinc finger protein transcripts, female sexual differentiation of the gonad and brain might result,” Rosenfeld said. “It’s possibly it’s more of a potential gradient within these rodents, where you have to turn on all these other zinc finger protein transcripts in males to stimulate male sexual differentiation and compensate for the absence of SRY.”
With the potential extinction of Amami spiny rats on the horizon, furthering this research has a degree of urgency.
“By elucidating more of the mechanisms in this endangered species, I think it might help us save the species or facilitate them being bred in captivity,” Rosenfeld said.
She hopes this research will continue with her team fully sequencing the genome of the Amami spiny rats to look more closely at what’s going on and how that might lead to a better understanding of the nuances of how animals without a Y chromosome undergoes male sexual differentiation.
“If you move outside the mammals, there are all sorts of sex chromosomes and exceptions like the duckbill platypus who has five sets of X and Y, and they can’t find differences between males and females,” Rosenfeld said. “People are focused on sex chromosomes and the SRY gene that they might be forgetting other contributing factors. By understanding these anomalous species, it opens up the idea that the mechanisms regulating gonadal and brain sexual differentiation are quite complex and not fully understood.”
Science and invention are both about discovering the possibilities in something.
Those possibilities can create something new that improves the lives of people and advances our understanding of the world.
It’s no surprise that Gary Stacey, a Bond Life Sciences Center primary investigator, is being recognized this year as one of 148 academic fellows by the National Academy of Inventors.
“I am very proud to welcome another class of outstanding NAI Fellows, whose collective achievements have helped shape the future and who each day work to improve our world,” said Paul R. Sanberg, President of the NAI. “Each of these new NAI Fellows embodies the Academy’s mission through their dedication, creativity and inventive spirit. I look forward to working collaboratively with the new NAI Fellows in growing a global culture of innovation.”
Stacey has spent years focused on the basic science behind biological phenomena including the relationship between bacteria and the roots of nitrogen-fixing plants. His work has explored the specifics of how plants can benefit from interacting with particular bacterium like Bradyrhizobium japonicum.
“This bacterium infects the roots of soybean and established a beneficial, nitrogen fixing symbiosis,” said Stacey, a Curators’ Distinguished Professor of Plant Science in MU’s College of Agriculture, Food and Natural Resources. “The two patents that describe these discoveries formed the basis for the Optimize product, which is now sold by Novozymes.”
When seeds of soybeans or other legumes are treated with Optimize, it encourages what’s natural by giving the future plant the opportunity to build a beneficial relationship with the bacterium. The bacterium infects the roots and creates nodules that “fix” atmospheric nitrogen, providing food for the plant that replaces some need for fertilizer. This improves plant growth and yield in an environmentally-friendly way and leaves us in a better position to feed the world in a sustainable fashion.
While his research has a significant potential economic plus side, Stacey points out that understanding the basic mechanisms underpinning how these plants and bacteria interact.
“Our goals are not to develop intellectual property or products, however, we remain cognizant of any possible applications of our research,” he said. “Beyond the exhilaration of making a basic discovery, it is also gratifying when you see the result of your labors being put to practical use as things move from discovery, through translation to ultimate application. I have been lucky in my career to be able to traverse this full spectrum of research.”
A natural curiosity connects the diverse scientists behind discoveries. That trait started young for Stacey.
“You could see signs of this when I was a small boy constantly turning over rocks just to see what was underneath. In a way, with my research, I continue to ‘turn over rocks’ for the sole purpose of just knowing what is hidden below,” Stacey said. “Although I must on many occasions justify my research in the context of impact or application, the truth is I do science for the sole purpose of satisfying my curiosity, and studies have confirmed that curiosity-driven research is the most effective at making major discoveries and exhibits a much higher return on investment.”
With 13 patents to his name, Stacey’s curiosity has allowed his science to thrive at MU.
“A research lab at a major university is really equivalent to a small business — with 20 employees my lab would qualify in the upper 50 percent of all small businesses in Missouri — and I encounter many of the same issues that any small business would have,” Stacey said. “I relish the challenge of being a scientist in which you are tested in so many ways…as an innovator, organizer, manager, communicator and entrepreneur.”
Election to NAI Fellow status is the highest professional distinction accorded solely to academic inventors who have demonstrated a prolific spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society.There are now over 1,000 NAI Fellows, representing more than 250 research universities and government and non-profit research institutes. The 2018 Fellows are named inventors on nearly 4,000 issued U.S. patents.
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About the National Academy of Inventors The National Academy of Inventors is a member organization comprising U.S. and international universities, and governmental and non-profit research institutes, with over 4,000 individual inventor members and Fellows spanning more than 250 institutions worldwide. It was founded in 2010 at the University of South Florida to recognize and encourage inventors with patents issued from the U.S. Patent and Trademark Office, enhance the visibility of academic technology and innovation, encourage the disclosure of intellectual property, educate and mentor innovative students, and translate the inventions of its members to benefit society. The NAI publishes the multidisciplinary journal, Technology & Innovation. www.academyofinventors.org
The 2018 NAI Fellows will be highlighted with a full page announcement in the Jan. 25, 2019 issue of The Chronicle of Higher Education and in upcoming issues of Technology & Innovation.
The complete list of NAI Fellows is available on the NAI website.
Wes Warren (left), Bing Yang (middle) and Ron Mittler (right) recently joined Bond LSC as primary investigators. | photos by Erica Overfelt and Roger Meissen, Bond LSC
By Roger Meissen | Bond LSC
Like with any family, a new addition brings possibility and excitement.
For Bond LSC, three new faculty promise to enrich research at the University of Missouri by working together across disciplines. Ron Mittler, Wes Warren and Bing Yang all joined Bond LSC recently to continue their research careers.
Bond LSC Interim Director Walter Gassmann said these strategic hires are years in the making and represent how departments and centers come together with a unified goal for MU.
“These are some of the first hires we’ve completed specifically looking at how new faculty could bridge individual research strengths that exist on campus,” he said. “These scientists can bring those strengths together to go in a new direction, and Bond LSC is the perfect place for these faculty to achieve their goals.”
Each researcher comes with a reputation that precedes him. It only takes one look at the framed covers of Nature Magazine lined up in a row in Wes Warren’s office to see evidence of that. The comparative geneticist was recruited from Washington University and has published work in Nature that sequenced the genomes of animals from the orangutan and the gibbon to the elephant shark and the platypus.
“My passion is to crack the black box of the genome and try to find weird and unique traits of various animals,” Warren said. “It’s not enough now to sequence a genome and compare it to others, you have to dig deeper, do wet lab work and try to validate your findings.”
His shared appointment as a Bond LSC investigator and professor of genomics in the Department of Animal Sciences, College of Agriculture, Food and Natural Resources, in conjunction with the School of Medicine, College of Veterinary Medicine and the MU Informatics Institute, gives him the opportunity to more easily move his research forward.
“My thought is that I can act as a liaison between researchers in these areas,” he said. “I want to keep in mind trait evolution and use that divergence in traits to practice evolutionary comparative medicine to think about disease in humans and companion animals.”
Yang brings a different expertise from Iowa State University where he spent years studying bacterial diseases of rice. His joint appointment as a professor of plant sciences comes from a partnership with the Donald Danforth Plant Science Center in St. Louis. His research began by looking at plant disease from the bacterial side, but has evolved to also study its host’s interaction.
“Over half the world’s population eats rice as a staple food and by understanding its basic biology we can engineer better rice varieties with disease resistance and yield improvements,” Yang said. “This joint appointment gives me a bigger scientific community and access to more tools to continue my former research while thinking about some high risk, high reward projects that no one has done before.”
Mittler brings a different expertise in plant science to Bond LSC. Most recently at the University of North Texas, his work focused on cell-to-cell communication and how plants respond to multiple stressors — like heat and drought — at the same time. To do this, Mittler studies proteins with unknown functions. One he identified in plants deals with reactive oxygen species, which is a type of oxygen that becomes activated and can cause damage within cells in its toxic forms.
“We don’t really know what 20 percent of the proteins in our body do and in plants it’s more than that,” he said. “One of them was very interesting to me because it responded to reactive oxygen species in Arabidopsis plants, and we found out that a close relative of this protein is found in humans and accumulates to high levels in cancer cells.”
This has led Mittler to expand his work into mammalian cells and will encourage partnerships outside of plant science. With the cancer connection in mind, Mittler has a joint appointment in the Department of Surgery in the School of Medicine
“This is one of the few places in the U.S. that has a medical school, a veterinary school, college of agriculture and a nuclear reactor, so you have a lot of resources available to you, and here I have access to crop fields I didn’t have before and people who do a lot of crop physiology,” Mittler said. “The biggest thing I’ve found here so far is that there is a big drive for collaboration and the walls and barriers between different departments are low. Not a lot of places have this kind of attitude.”
The emphasis on connections across disciplines is key to the larger research goals within the University of Missouri System.
“It’s the research community, the facilities and resources that convince excellent researchers like these to join our research enterprise, and Bond LSC is the perfect place to have faculty from five colleges bump into each other on a daily basis,” said Mark McIntosh, vice chancellor of research, graduate studies and economic development at MU and vice president of research and economic development for the UM System. “Collaborative research is more competitive when it comes to grant applications to federal agencies, and is more likely to lead to innovations and economic development. Our success with interdisciplinary collaborations — like those in the Bond LSC — is the motivation for our focus on building the Translational Precision Medicine Complex (TPMC). I look forward to seeing how our new Bond LSC investigators can build and nurture these partnerships.”
For scientists, studying a disease presents a puzzle looking for an answer, but there are real people behind the research that may one day cure the illnesses that turned their lives upside down. Chris Lorson and Monir Shababi work on one of these puzzles in Bond LSC.
Find out more about their work and the faces behind SMARD, a rare, often fatal, genetic motor neuron disease in the following story courtesy of the College of Veterinary Medicine.
Monir Shababi, an assistant research professor in veterinary pathobiology, and Christian Lorson, Bond LSC principal investigator, College of Veterinary Medicine professor and associate dean for research and graduate studies, have invested countless hours during the past five years to solving a cruel medical mystery. A family who has endured the agonizing ordeal of having two children born with the same disease has invested funding for the research being conducted at MU’s Bond Life Sciences Center.
Meet the Sims family: mother, Jill Sims, MD; daughter, Caroline; father, Eric, an associate professor of economics at Notre Dame; daughter, Molly; and daughter, Catherine, who turned 5 in August. Catherine is living with a rare genetic disorder called Spinal Muscular Atrophy with Respiratory Distress, or SMARD. The Sims had another child, Bobby, who was born in 2012 and died of SMARD after a month of life.
The disease is called spinal muscle atrophy with respiratory distress, or SMARD. SMARD is a progressive motor neuron disease that has no treatment or cure. At least, not yet.
Shababi, PhD, and Lorson, PhD, and the Sims family — mother Jill, father Eric, grandparents Grant and Patricia — have teamed up in an effort to change that.
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The disease is so rare that it is largely unknown, even to most medical professionals. When you are the parent of a child with SMARD, you are in a daily, nonstop, life-and-death struggle.
It is exhausting. It is frustrating. It is a battle that requires an endless reserve of endurance and willpower. And, it requires cutting-edge, scientific discoveries that are just coming to light at MU’s Bond Life Sciences Center.
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Catherine Sims lives on a ventilator and needs around-the-clock care. Yet, now age 5, her life is a victory.
“Our first daughter was born healthy, so we had no idea that we carried such a terrible disease,” Jill Sims says. “Then, our second child, Bobby, — who is named after my dad — was born very small, which was unusual given our family history, and he was very quiet as an infant. Those were the only things I noticed. He was three weeks old and we were driving back from Thanksgiving at my parents’ house. I fed him and put him in his car seat. I checked on him 30 minutes later and he had died. He had aspirated. The disease causes the diaphragm not to work, so he couldn’t breathe and eat at the same time.”
Despite requiring mechanical ventilation and around-the-clock care, Catherine attends school, enjoys family outings and participates in activities as much as possible.
Bobby Sims, born Oct. 31, 2012, died on Nov. 30, 2012. His death was attributed to unknown respiratory failure, and he was considered a victim of Sudden Infant Death Syndrome (SIDS). Catherine Sims was born in August 2013; her diagnosis came four months later.
“I went on to have Catherine next, and then we knew something was up,” Sims says. “Catherine was very similar to Bobby, very small and very quiet. That, of course, led us to figure out something was going on.
“In the period of time when Catherine was having problems and was hospitalized but undiagnosed, Catherine had a test done that put her group of symptoms into a specific category of neuromuscular diseases,” Sims says. “A good friend of mine Googled that category and the search produced a WordPress blog that Lisa Porter Werner had contributed to.”
The blog contained personal stories of families who had children with a disease named SMARD. The goal of the blog was to put SMARD on the radar, for families who didn’t have a diagnosis and needed to find answers as well as find support. Porter Werner had posted her own family’s story.
“My friend forwarded me Lisa’s particular story regarding her two children with SMARD, and the story almost identically matched my own,” Sims recalls.
Porter had read extensively and combed the internet for information and cases similar to those of her children. Porter eventually found a modicum of information about something called SMARD, which had been diagnosed in approximately 60 children.
“Lisa Porter’s blog contained the personal stories of families who had children with SMARD,” Sims recalls. “My friend forwarded me Lisa’s particular story regarding her two children with SMARD, and the story almost identically matched my own.
Living with SMARD, a progressive motor neuron disease, means Catherine needs 24/7 care from her family and home-health attendants.
“The Werner’s first daughter died at six weeks of age. It was called a SIDS case; she just died in her sleep,” Sims says. “They had Silas, their son who is living with SMARD, shortly thereafter and she put him in a sleep study when he was three weeks old. She said, ‘No, my daughter didn’t just die. There was a reason.’ It turned out that Silas was having major breathing problems during sleep.
“I was convinced after reading about Lisa’s family that my two children had SMARD as well, and I asked Catherine’s doctors to test her for it,” Sims says. “Catherine’s test came back positive four weeks later. A year or so later, I connected with Lisa through a Facebook group for families with children with SMARD. We began talking more, once my in-laws funded SMARD research at the Jackson Lab, and continued to talk once we found out about Dr. Shababi’s paper that came out in 2016.”
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In order to know what SMARD is, it is important to know what it is not. Despite the obvious similarities in name, spinal muscular atrophy (SMA) and spinal muscular atrophy with respiratory distress have sharp differences.
Both conditions affect the lower motor neuron cells of the spinal cord that control voluntary muscle activities like walking, talking, breathing and swallowing. Both are sometimes characterized as “like ALS in babies.”
SMA, which can range from type 1-4, is caused by mutations in or the absence of the SMN1 gene. SMA typically causes weakness in the core first and the baby or child may present as hypotonic, or having low muscle tone — sometimes called floppy baby syndrome. Babies or children with SMA may eventually develop respiratory compromise over time.
SMA is the leading genetic killer of infants; one in 40 people are carriers of SMA.
SMARD, in contrast, is extremely rare. The exact number of cases is unknown, but it has clearly occurred in more than the approximately 100 children worldwide who now carry that tragic diagnosis. SMARD is branded an “orphan” disease, a term commonly applied to any debilitating medical condition that affects fewer than 200,000 Americans. There is little information and few resources available regarding SMARD.
The Sims sisters: Catherine, a SMARD survivor, with older sister Molly and younger sister Caroline. Catherine is standing with the aid of a device.
SMARD is a genetic disease, caused by mutations or loss of the IGHMBP2 gene, Immunoglobulin MU-binding protein 2. The condition is inherited in a recessive pattern, meaning both parents must be carriers of the gene mutation and each parent must pass along a copy of the mutation in order for the child to be affected. In essence, every time two carriers have a baby, there is a one in four chance their child will be affected.
Onset of the disease usually occurs suddenly, in what seems to be an otherwise healthy baby, typically between 6 weeks and 6 months of age. Once the diaphragm is paralyzed, the infant must depend on their accessory muscles to breathe. These muscles also weaken as the disease progresses, until the child needs mechanical ventilation.
Many children die in the first year of life, often in their sleep or from a respiratory illness. Past the age of 1 year, almost all children living with SMARD require a tracheostomy, a ventilator and a wheelchair.
Simply put, SMA usually presents as a hypotonic or “floppy” baby who gradually develops respiratory distress. SMARD presents as a baby in respiratory distress who gradually becomes hypotonic.
SMA and SMARD share a similarity in that both are monogenic disorders, conditions caused by mutations or loss of a single gene. Shababi and Lorson have an established history of working with SMA. Now, their focus is SMARD.
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“In 2009 and 2010, a lab at the Ohio State University used a viral vector to introduce the SMN gene in SMA mice,” Shababi, the CVM researcher, says. “The viral vector does not contain the necessary genes required for the virus to cause infectious disease. You can replace viral genes with the specific gene you want and keep only the part of the virus that is required to enter the body, find its receptor and produce the desired protein from the gene it carries.
“They (researchers at Ohio State) put a human SMN gene into a viral vector — adeno-associated virus 9 (AAV9) — that has the potential to pass the blood brain barrier in humans. This virus has the capability to enter into the brain, the spinal cord, muscles and peripheral organs,” Shababi continues. “The AAV9 virus carrying the SMN gene was injected into SMA mice. They were able to rescue the affected mice. That was a huge step toward treating SMA. That vector is currently in Phase 2 clinical trials with AveXis/Novartis.
“With SMARD, there is also a single gene involved in the disease — the IGHMBP2 gene,” Shababi continues. “So, we took a human IGHMBP2 gene, in the form of cDNA, and placed it into the same AAV9 vector and injected it into the brain of SMARD pups that were 2 days of age. Our virus did the job and the SMARD mice were cured.”
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Catherine and older sister Molly sporting festival face paint.
“Dr. Shababi posted a paper, I believe in March 2016, that reported the results of her work on SMARD,” Sims says. “Lisa found the paper and contacted Dr. Shababi and had a wonderful reception. They had several very long conversations about what Monir was doing, what she had already been doing, and they immediately had a strong connection.
“Dr. Shababi was very personable over the phone, and was very passionate and very approachable about her work,” Sims relates. “Sometimes, it’s hard to get ahold of people, but Monir answers her own phone, and she was very clear with Lisa about what had already been done, which was pretty cool for us because we didn’t know — we didn’t realize how much work Dr. Shababi and Dr. Lorson had already done on SMARD. We were impressed by how much of a handle they already had on the disease. They were ahead of the game. That was great news for us on the family side; at the time, we were aware of only one other lab in the country — the Jackson Lab in Maine — doing work in this area. We couldn’t believe that, wow, there’s a second lab and they are already in gear, they already have a lot of good things going.
“Then, Lisa got me in the loop with Monir, and I talked to her a few times,” Sims continues. “They were having a funding issue, which is not surprising because of how rare the disease is. When we first learned about the work being done at the Jackson Lab, my in-laws agreed to fund SMARD research at Jackson. After learning what Dr. Shababi and Dr. Lorson were doing, I talked to my in-laws again and asked if they would be interested in funding Monir’s research. My father-in-law and I had a few conversations with Monir and Chris Lorson, and then my in-laws decided to do another fund, this time at Missouri, that started this past December.”
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“If you look back a number of years, there has been a gene therapy on the translational side that has had exceptionally powerful results in SMA,” says Lorson. “AveXis now has a Phase 2 clinical trial going for their gene therapy product, which has the potential to be very impactful. It has demonstrated efficacy in SMA, but also provides an important proof of principle for gene therapy as a whole. So, it was really exciting to know that there’s only one gene responsible for each of these horribly devastating diseases, SMA and SMARD. It allows you to consider following a similar path. Knowing that, Monir started developing a project that was gene therapy, gene replacement for SMARD.
“Whenever I talk about this, I give about 110 percent of the credit to Monir,” Lorson explains. “Monir has really been the driver of this entire project. Originally, I said, ‘Monir, I’d really like you to develop this gene therapy for SMARD, I think it’s a really exciting area of research. I’ll check back in about six months.’ When I did, we had the mice, we had the vector and she was doing the experiments. That’s exactly the kind of gumption that you hope to find. She did all of that. My role was to say, ‘Good job, Monir!’
“She was the first author on an important paper in Molecular Therapy published in 2016,” Lorson continues. “Based upon that, and the level of excitement, people found her. Through Facebook and Facebook friends, they started to communicate back and forth. Monir is driving it. Monir is doing it.
“AAV9 is in clinic for a number of other diseases, but every time you put a new gene in, you have to go through the Food and Drug Administration,” Lorson says. “That’s why the process isn’t as simple as it might appear to be. Every single time you change that vector — that gene delivery vehicle — you have to get it approved.”
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“My in-laws have been very generous, but you need a lot of capital to do this research,” Jill Sims says. “SMARD is so rare that progress will probably come only from academic research. You really need a lot of support and you need a lot of funding from various sources. Right now, our life continues the same. It’s great that everybody is doing this great research, but you need so much more for a cure. That’s what everybody wants; we want our kids to be normal.
“A day in the life of someone with SMARD is very difficult,” Sims says. “There’s a lot that has to be done to have a normal life, and there are a lot of obstacles to that, so you’re constantly trying to overcome those.
“This disease is devastating,” Sims continues. “It can take away every basic human function: the ability to sit, crawl, stand, walk, talk, swallow, feed oneself, clean oneself, use writing utensils and so on. The disease also makes the person more likely to have respiratory problems since they can’t breathe or even cough on their own. It is hard as a parent. Every day we live with the potential fatality of this disease. If their trach tubes come out, they cannot breathe. These trachs sit in their windpipes, held in by ties, like a tight necklace. It is not secure.
“You may go months without anything happening then, all of a sudden, it’s coming out. When that happens, she may only have 60 or so seconds to live,” Sims says. ”You have to have someone always watching them, either a specially trained nurse or a parent, who is a trained caregiver.
“That’s the hard part that we always live with,” says Sims. “Yes, she looks good, and she goes to school, and she’s in activities, to some degree. We adapt everything so she can do as much as possible. But, she is living with a fatal disease that is non-treatable. We basically just manage her symptoms. We know very well that we could lose a second child. That’s what is hardest on us. Even though there are these great advances, she is alive because of amazing machines. Every day presents the chance that she could die.
“When we take Catherine places, there are always at least 10 machines that go with her,” Sims says. “Everything just takes longer. We have a special van with a lift, because she’s in a wheelchair. You are in the thick of trying to make what is not normal to be normal.
“You can’t just pick up your child and go, you can’t feed them a different way, or put a different outfit on them,” Sims continues. “Those are the silly things I took for granted having had a healthy child before. I just did her hair, brushed her teeth, and put her in whatever, and fed her whatever I wanted. Catherine cannot do that. It’s the small things that you take for granted, and there are so many ‘small’ things. We are fortunate to have excellent in-home nursing care, but this also means that my husband and I have had to sacrifice a lot of our privacy. And, I’ve had to give up a lot of my mothering, because I have someone else that always needs to know what I’m doing. That’s hard.
“So, we want a cure,” Sims states. “We are all in. We are always fighting the disease. Our goal would be to have a cure as fast as possible, because the older the kids get, the less chance you have of curing them. This is a neurologic disease; it is hard to get those nerves back. We realize that our kids may be too old. Catherine will be 5; Lisa’s Silas is 8 or 9. They’re kind of old. The ideal time would be right at birth or shortly thereafter. So, that’s what we want. We want the big places — the big funding sources — to realize how important this is, even though it affects only a small number of people.”
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“Our gene therapy vector is a very powerful tool,” Lorson says. “It is early days, in terms of trying to push it to the clinic, but we’re trying to do all the important pre-clinical questions.
“There are a number of questions you have to ask,” Lorson continues. “When do you deliver that kind of vector? Does it work only if you do it right at birth, before disease develops? Can you correct the disease, in other words, once the research animals have the disease, can you bring them back to more of a normal state? Or, once that happens, is it just too late for something like gene therapy? We want to deliver what they want to see, in terms of working hard and getting results out. That is what we are trying to do.
“I want to say, ‘Thank you,’ in the biggest way possible to the Sims family,” Lorson says. “Their generosity is really amazing. We consider this an exceptional honor. We want to be the best stewards they could possibly find, of their trust and of their funds. People go out and raise these funds — in some cases, through car washes and bake sales — so you have to put a particularly high value on those dollars. My fondest hope is that we do that every day.”
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