Ron Mittler always thought he would be a veterinarian, until he was exposed to the lab.
“I went to school to be a vet,” Mittler said. “I made the mistake of working in the lab to make money in the summer and I got hooked on research. I worked with plants and I realized it is the best job to have for me.”
That “mistake” has turned into a career of research and teaching in academia. The latest chapter in that journey started in July when Mittler joined Bond LSC as a professor of plant sciences at Mizzou.
Mittler’s research started with a focus on plants, digging into cell to cell signaling systems.
“I’m looking at how different cells within the same organism communicate with each other, how signals can be transferred and how plants respond to stress by activating cell-to-cell communication,” Mittler said. “For example, you take a plant and apply stress to one leaf to the entire plant will resist. But, I’m really interested in how plants acclimate to a combination of different stressors like drought and heat or heat and salinity together instead of looking at just one stressor.”
As Mittler has let the questions dictate his research, his foundation in plant signaling proteins has expanded beyond plants.
“I was only working on plants,” Mittler said. “I had a project discovering the unknown function of proteins in plants. About 20 percent of the proteins in our body, we don’t know what they do. My project was to try to figure out what all the proteins in plants do. It was very interesting to me, we found out a very close relative of a plant protein is in humans and accumulates cancer cells.”
This connection lends itself well to creating a bridge between his plant science research and research on cancer at MU’s School of Medicine. This potential collaboration and the opportunity to study plant stress in a crop setting swayed his decision to join MU. He comes from University of North Texas where he was a professor in their biological sciences department and earned his bachelors and masters in botany at Hebrew University. He then earned his Ph.D. in Biochemistry at Rutgers
A key focus of Mittler’s past work has been on reactive oxygen species (ROS). ROS can be found in biological processes in both plants and animals. Mittler shed significant light on the ROS wave, and the role the wave plays in stress response in plants. Essentially, it is a mechanism for cells to communicate where the ROS within a cell stimulate the cell next to it, creating a domino effect, or wave, that sends a message to nearby cells.
Mittler will be researching how these Reactive Oxygen Species and iron play a role in human disease.
“We are working on a group of proteins that regulate iron and Reactive Oxygen Species in cells,” Mittler said. “That is in relation to cancer or diabetes. Those proteins play a role in cancer cells. We are studying how and why these proteins are so important and trying to develop drugs that target these proteins.”
Questions may be the reason Mittler has taken so many turns in his research, but they are also what kept him motivated in research.
“It’s exciting, answering questions no one has answered,” Mittler said. “Like a little boy, it is tinkering with things and trying to figure out how things work. It is like detective work for me, seeing how plants work, how the body works.”
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.”
If you would like to help in the battle against diseases that could someday be relieved through gene therapy, please visit this page.
When you walk into Wes Warren’s office you may notice the Charles Darwin bobble head, or the platypus on the cover of Nature magazine or even the shelf of colorful books in the corner.
At every glance, you’ll probably see a picture of a different kind of animal.
Animals aren’t just a passion for Warren, they are the target of his research. Over the past 17 years, he has worked with around: 10 mammals, 6 bird species, 10 fish genomes, five different species of Tsetse fly, sand fly, even the common house fly, and that’s just the beginning.
Warren deciphers the genetic codes in each species to better understand them and how these blueprints of life give us insight into the genes in humans to help better understand disease prevention.
“I try to keep in mind the question on how the trait evolved and more importantly the similarities in this trait to human diseases,” Warren said. “It’s important that we understand the genetic code of as many species as possible. If we are going to understand not only how to conserve these species and their environment’s we must also understand their complex biology. The more comparative information we have on these genetic codes leads to a better understanding of their similarities and differences when studying disease origins. Why humans succumb to many types of disease and many animals don’t, remains a mystery.”
Growing up in Florida with a beef cattle family business, Warren always thought he would be a vet. He went to Oklahoma State University for Animal Sciences in hopes of becoming a large animal vet, until he realized his fascination with research. He then went to Clemson University and got a masters in Reproductive Physiology. For his Ph.D. Warren then came to MU and studied Molecular Endocrinology, again in the Animal Sciences field.
And Warren came back here to his alma mater just a couple weeks ago to start his own lab.
“In general the reason I liked the location of Bond LSC was when I was recruited here the thought was I would be the liaison between med, vet and animal schools,” Warren said. “The appealing thing of coming here is the vet school, animal sciences studying domesticated animal genetics and you have the med school doing personalized medicine.”
Warren’s lab may not be set up until the end of this year, but he is excited to make advances in his research.
“One of my objectives at MU is to practice evolutionary medicine,” Warren said. “In an environment that embraces this comparative approach, that really excited me about coming here, and to keep my intellectual fire burning.”
Before coming to Bond LSC, Warren spent his first career years at Monsanto and then felt the need to return to Academia. At Monsanto most of his research was in molecular biology. He also continues to collaborate with the St. Louis Zoo on the unknown causes of high incidences of pyometra urinary in African Painted Dogs.
Warren has published over 130 research articles. The number will only grow as he continues and begins his many collaborative research projects and new research at Bond LSC
“It is very exciting to open that black box of a new genome,” Warren said. “You are the first one to see the codes of life in that species, learning the evolutionary history of each genome and sharing in these exciting discoveries with your fellow scientists. This never gets old.”
From his childhood in China where his father farmed the crop to more than 20 years of research on the staple, it’s more than just food.
“Rice by itself is the major crop in the world,” said Yang, one of Bond LSC’s newest researchers. “It provides more than half of the population’s food. Rice is a model crop species and can be used for other crop plants. It can be applicable to other crop species since it is easy to study.”
Originally from Southwestern China, Yang initially went to college at Southwest Forestry College in China and later came to the U.S. for the opportunity to further his education. He studied bacterial blight in rice at Kansas State University and received his Ph.D. in Plant Pathology. He continued this research at Iowa State University where studied genome editing, eventually becoming a professor in Genetics, Development and Cell Biology. He joined MU as a professor of Plant Sciences and joint hire for the Donald Danforth Plant Science Center and Bond LSC.
“I worked at ISU for 12 years and my research in my lab used bacterial blight in rice as a model system,” Yang said. “I started looking at rice from bacterial side and then expanded to look at the host interaction. The possibility for new discovery keeps me excited about the work.”
Bacterial blight is a deadly disease that can kill up to 75 percent of a rice crop. While Yang focuses on this pathogen, his research can expand understanding of the molecular mechanisms behind various plant diseases in a number of crops. Yang hopes his genome editing paves a way to create a more disease resistant plant.
“Especially with the advanced technology we can engineer some crop and rice varieties with better resistance,” Yang said.
But this research is more than new discoveries, it’s a part of who Yang is.
“Rice and the disease relate to my background,” Yang said. “I am from a family in a southwest province of China where we were rice farmers.”
While his lab area may be bare for now, in a few months’ new advances will come with getting his lab up and running on the third floor of Bond LSC.
“It is a challenge to move the whole lab,” Yang said. “But another aspect for this move is we can do some high risk projects. This means nobody has done it before. High risk also means high possibility for failure.”
But failure doesn’t scare Yang.
“Science always means some success, but you also have to fail for scientific research,” Yang said. “To me, science means using some approach or tool to uncover the mystery behind how to make something better.”
When Brittany Cruzan does her laundry, she can’t stop thinking about science.
“Science controls our everyday life,” Cruzan said. “Coffee, tea, the way you cut your hair, it’s all science. I’ve liked science since I was a kid. I am obsessed with knowing how things work. I don’t care why but I care for how.
Cruzan applies that desire to know how things work to work in the lab. From her first semester of freshman year to now as a junior, Cruzan been in Mannie Liscum’s lab chasing the how behind the science.
“Freshman year I was sterilizing water and this year I am creating mutations in plants” Cruzan said. “I went from making water and dirt to now making a living organism. I am definitely getting a lot of guidance from grad students but it is exciting to feel independent.”
The lab uses Arabidopsis as their model plant to study its growth and how the plant responds directionally to light. This research can aid scientist in enhancing plant growth in drought and other circumstances, and they use mutations to explore which genes might create characteristics that are more resilient to stress in the environment. Now that Cruzan has her own project it’s easier for her to realize the potential impact this research has on others.
“I am researching to find the maximum potential for plant growth and maximize the output for agriculture,” Cruzan said. “Once we figure this out it could mean more corn, more cows and more full bellies.”
After college Cruzan wants to continue impacting lives. She plans to volunteer before she applies to med school, and she believes life is full of endless possibilities.
“I don’t even know what I’m supposed to do, but I want to make people happy,” Cruzan said. “Anything I can do for the greater good makes me sleep better, whether that is volunteering or doing research to feed the world.”
For now, you can find Cruzan in the lab focused on a way to improve plant growth.
“I don’t think I personally will get far enough to solve world hunger, but if we can figure out a plants growth then we can add to all the research being done,” Cruzan said. “I believe that research creates the world of tomorrow, and while it may seem small today, in 5 years it could change a life.”
