Translating soybean cyst nematode research

Roger Meissen/Bond Life Sciences Center -  These soybean roots show some nematode cysts. The small, white circles are the hardened body of the nematodes and form when the nematode attaches itself to the root to create a feeding cell.

Roger Meissen/Bond Life Sciences Center – These soybean roots show some nematode cysts. The small, white circles are the hardened body of the nematodes and form when the nematode attaches itself to the root to create a feeding cell.

Beneath a North Carolina field in 1954, a tiny worm inched its way through the soil and butted against a soybean root. The worm pierced the plant, slipped inside and inserted a needle-like appendage into a cell. It pumped a mixture of proteins into the root cell and waited for the potent blend to take effect on the unsuspecting soybean.

Since the first detection of soybean cyst nematode (SCN) in the US, the worm Heterodera glycines has spread to about 80 percent of American soybean fields. In Missouri, SCN attacks soybeans in almost every county and causes decreased yields even in robust, healthy-looking fields. Nationwide, SCN wreaks havoc to the tune of $1.2 billion per year, making it by far the most costly soybean pest.

Despite the hefty toll, farmers still depend on the same small handful of resistant soybean varieties to combat SCN that they have used for years. But those natural defenses are becoming less effective as nematodes evolve.

“More than 90 percent of the soybean cultivars that farmers plant derive their resistance from a single source,” said Melissa Mitchum, a plant nematologist at the University of Missouri Bond Life Sciences Center and Division of Plant Sciences faculty member in the College of Agriculture, Food and Natural Resources. “Consequently, this has led to widespread virulence in the pathogen population, thereby reducing the effectiveness of those resistant cultivars.”

But in the past 10 years, researchers studying SCN have made numerous breakthroughs, unlocking the secrets of the nematode and exploring how the worm interacts with host plants. Now, scientists are poised to bring that knowledge from the laboratory to the field.

Found in translation

Relatively little was known about SCN a decade ago.

Scientists could determine the type of nematode in a soil sample and had just figured out the cocktail of proteins a nematode pumps into the soy root cell that transform it into a syncytium, or feeding cell.

Working in part with funding from commodity boards and farmer checkoff dollars, researchers around the country made breakthrough after breakthrough, deepening our understanding of SCN and equipping scientists with new tools to fight the pest.

That money helped scientists sequence the soybean genome, draft a SCN genome and pinpoint important soy and SCN genes.

Checkoff investments continued to pay dividends in 2012 when Mitchum and colleagues cloned the first gene linked to natural soybean cyst nematode resistance. This breakthrough is one key step in moving science from the laboratory into the field. With a SCN resistance gene in hand, new avenues for creating soybean varieties that fight off the nematode are opening up.

But other areas of research also hold promise in the struggle against soybean cyst nematode’s parasitic ways.

Mitchum’s group also identified the plant receptors that recognize and respond to the blend of proteins an attacking nematode inserts into a plant. In a recent project published in Plant Biotechnology Journal, Xiaoli Guo, a postdoctoral fellow in Mitchum’s lab demonstrated that silencing those receptors in soybean roots helped the plant resist SCN.

This work has implications for more crops than just soybeans: Working with collaborator Xiaohong Wang at Cornell, Mitchum’s group used their understanding of plant receptors to develop a potato resistant to potato cyst nematode.

A roadmap for discovery

To build on the momentum of recent research, experts drafted a roadmap for the next decade of nematode research. Their goal, Mitchum said, is to address the challenge of translating these research breakthroughs into something tangible for the farmer.

With support from state farmer run organizations such as the Missouri Soybean Merchandising Council, the North Central Soybean Research Program and the United Soybean Board, researchers are formulating teams that “bring together commodity, industry and university funding to develop collaborative, interdisciplinary, multistate projects,” said Mitchum.

And there’s plenty of scientific firepower to advance research: MU’s College of Agriculture, Food and Natural Resources alone has more than 90 faculty studying plant science, plant genetics and other areas of agriculture-related science.

The scientists’ plan for the next 10 years involves a blend of molecular research, plant breeding, population biology and outreach. Researchers will focus on refining the existing draft SCN genome, which will help to develop a quick, inexpensive test for HG type and eventually contribute to understanding of how SCN overcomes a plant’s resistance. They’ll create an “atlas” of SCN genes researchers can use to block the pest. Updating yield loss estimates and mapping SCN distribution will also give scientists a better idea of the nematode’s national impact. Other efforts will allow breeders to incorporate new sources of resistance into commercially-available varieties, refine the use of non-host species to control SCN and develop a pipeline for creating and testing transgenic SCN-resistant soybeans. Finally, videos, webinars and training modules will help scientists, students and producers take advantage of new discoveries and techniques.

Roger Meissen/Bond Life Sciences Center -  Michael Gardner, Ph.D. student, Melissa Mitchum, associate professor of Plant Sciences, Xiaoli Guo, post doctoral fellow, conduct research at the University of Missouri. They investigate how soybean cyst nematode overcomes soybean resistance to identify novel approaches for management.

Roger Meissen/Bond Life Sciences Center – Michael Gardner, Ph.D. student, Melissa Mitchum, associate professor of Plant Sciences, Xiaoli Guo, post doctoral fellow, conduct research at the University of Missouri. They investigate how soybean cyst nematode overcomes soybean resistance to identify novel approaches for management.

Onward with research

A thorough understanding of SCN resistance and virulence starts with basic research and then moves into the field. “We all need to come together to transfer this knowledge to the breeder,” Mitchum said, “and from there it gets out to the farmer.”

 Her lab recently received a National Science Foundation grant to continue their work on soybean protein receptors. Specific targeting of the receptors is just one potential strategy for producing new kinds of SCN-resistant plants. A second grant, from the National Institute of Food and Agriculture, will allow the lab to continue refining their understanding of how SCN proteins overcome a host plant’s defenses. To that end, Mitchum’s graduate student Michael Gardner is identifying the genetic blueprint of the different SCN types present in Missouri fields.

“If we better understand nematode populations and what makes those populations distinct, we can better advise farmers confronted with virulent nematodes,” Gardner said. “We’ll be able to go one step beyond the HG type test and understand how nematodes are able to adapt in the long term, not just the next growing season.”

But these breakthroughs do little good unless they then become useful tools for breeders and ultimately farmers. To that end, Mitchum and other researchers will help breeders use research results to produce soybeans with durable resistance. They‘ll also develop guides so farmers can easily incorporate new technologies and management strategies into their farms.

It’s important for farmers, breeders and researchers to take a unified approach to fighting SCN, Mitchum said, because a tactic that seems successful at first could backfire.

For instance, combining resistance genes in a single soybean variety could actually be harmful. “When we deploy it in the field, we select for nematodes that can overcome multiple types of resistance,” Mitchum said.

A better approach might be to perfect varieties with distinctive resistance mechanisms and insure durable resistance by rotating among the resistant varieties and non-host crops.

“It’s similar to taking antibiotics,” Mitchum said. “Improper use and overuse selects for resistance.” The strategic planning document should help everyone working with soybeans and SCN leverage and build upon new knowledge.

Despite all the research and recent breakthroughs, there remains only one certainty in the ongoing arms race between soybeans and SCN: “It is highly unlikely that we will eradicate it.” Mitchum said, “We’re going to have to find new strategies to protect and bolster soybean yields.”

Thanks to the efforts of researchers such as Mitchum, in the future SCN might be a little easier to get along with.



Roger Meissen/Bond Life Sciences Center - Research specialist and coordinator for the Plant Nematology Lab Amanda Howland processes soil samples for nematodes. Howland replaced Bob Heinz earlier this year.

Roger Meissen/Bond Life Sciences Center – Research specialist and coordinator for the Plant Nematology Lab Amanda Howland processes soil samples for nematodes. Howland replaced Bob Heinz earlier this year.

University of Missouri Plant Nematology Laboratory: An extensive legacy

Bob Heinz spent his last day at work in December surrounded by nematodes. Heinz served as Mitchum’s research specialist and coordinator of the Plant Nematology Laboratory, where he processed soil samples, responded to growers and assisted researchers. After 35 years on the job, he’s retired, and Amanda Howland is now filling his shoes. The scientists and farmers who’ve worked with Bob over the decades thank him for his dedication and wish him luck in his retirement. And Amanda: Welcome aboard.

The Plant Nematology Lab, housed within Mitchum’s lab at MU, represents a successful model for how research, teaching and extension program integration can promote interdisciplinary collaboration. Such an approach helps maintain an effective pipeline that brings research-based information and resources from MU to Missourians. The lab offers an array of tests that help farmers understand and manage nematode populations. The available tests include:

Vermiform Nematode Identification: Soybean Cyst? Root Knot? Lesion? Find out what kinds of nematodes are in your fields with this test.

Soybean Cyst Nematode Egg Count: This procedure provides an estimate of the number of SCN eggs in your field.

Soybean Cyst Nematode HG Type Test: Different types of SCN have overcome various sources of soybean resistance. A HG type test will help you determine the best source of resistance for the particular type of SCN in your field.

For more information, go to or contact the Lab.
Phone: 573-884-9118


Oliver Rando researches effect of fathers’ lifestyles on their children

How much does a newborn know about the world?

That can depend on their parents’ genes, according Oliver Rando, an epigeneticist at the University of Massachusetts.

Rando will speak Saturday, March 14, at 10:30 a.m. at the 11th Annual Life Sciences and Society Program at Bond LSC. His research focuses on how fathers’ lifestyles affect their children, one part of the symposium’s focus on epigenetics. Epigenetics is the study of how organisms change because of a modification in gene expression.

Rando is clear that his research is no more important than that of other scientists in his field.

“The field we work in is important since we and others have shown that a father’s lifestyle can potentially affect disease risk and other aspects of his children,” he said.

During his talk on Saturday, Rando will discuss a “paternal effect paradigm” based on experiments his lab conducted on male mice. The mice were fed different diets and mated with control females. Then researchers analyzed the metabolic effects that resulted in their offspring.

“In terms of the basic science aspects of the system, doing this sort of experiment with fathers rather than mothers is important, since mothers provide both an egg and a uterus to the child, whereas in many cases fathers only provide sperm,” Rando said. “So, with fathers you don’t have as many things to look at to find where the relevant information is.”

Scientists in his lab also study yeast and worms to understand epigenetic inheritance. They use molecular biology, genetic and genome-wide techniques to conduct the research.

For more information about Dr. Oliver Rando, read this Q&A from the Boston Globe.

Find more information about LSSP events and speakers at

Don’t stress, your kids will thank you

LSSP Symposium highlights epigenetics of the womb and how parental stress can change genetic makeup

Could a stressful day during pregnancy change the future of a developing child nestled in the womb?

Experts in the epigenetic research field are saying yes.

This weekend the 11th annual Life Sciences and Society Program will kick off “Epigenetic Revolution: Nature, Nurture and What Lies Ahead,” bringing experts on environmental influences on offspring to the stage.

Two speakers will focus their talks on the period of time developing mammals spend in the womb and what factors could trigger changes in their genetics. Tracy Bale, from the University of Pennsylvania, and Irva Hertz-Picciotto., from UC Davis, promise to draw the largest crowds.

“I heard great things about Tracy Bale’s innovative research — several senior colleagues called her a rising star in the field — so we were keen to invite her,” said LSSP Symposium Director Mary Shenk. “The connection to neurodevelopmental disorders like autism was of strong interest on campus.”

Epigenetic research has could provide answers to some of our longest standing questions.

Epigeneticists reason that the nature versus nurture development notion doesn’t consider their overlap. The premise is that our future is not only influenced by the genetics of our parents, but also tweaked further down the line by environmental factors.


Don’t miss it: Stress Parents

Tracy Bale, professor of neuroscience and animal biology at the University of Pennsylvania, will present "Stress Parents: Maternal and Paternal Epigenetic Programming of the Developing Brain" in Monsanto Auditorium at 9 am on Saturday.

Tracy Bale, professor of neuroscience and animal biology at the University of Pennsylvania, will present “Stress Parents: Maternal and Paternal Epigenetic Programming of the Developing Brain” in Monsanto Auditorium at 9 am on Saturday.

Tracy Bale will speak in Bond Life Sciences Center’s Monsanto Auditorium at 9 a.m. Saturday. Her talk, “Stress Parents: Maternal and paternal epigenetic programming of the developing brain,” will cover cutting-edge research at the University of Pennsylvania where she linked parental stress, infection and malnutrition to an increased risk for the childhood development of neurodevelopmental disorders, like autism and schizophrenia.

Bale’s research provides tools to better understand how parental experiences trigger changes in their future offspring’s brain, and they could play an important role in disease risk and resilience.

She tests her theories in mice, finding epigenetic marks that were changed by male mice stress experiences. She said the research could one day translate to humans.

“If we can identify epigenetic marks in mice that are important in how their offspring develop, we might be able to understand more about human lifetime exposures to things like stress and how important such marks are in germ cells,” Bale said.

The bottom line is epigenetics can do what evolution does, but much more quickly. Bale wants the audience to walk away from her talk on Saturday morning understanding the importance of germ cells and how the influence of the environment can impact future offspring.

“This field helps to explain how an organism can rapidly respond to a changing environment and pass on potentially beneficial traits to future generations without the length of time evolution would require for such fitness,” Bale said.


Don’t miss it: Epigenetics and autism

Hertz-Picciotto will turn our discussion toward the topic of Autism: Past Evidence, Current Research and future quandaries” at 2:15 p.m. Saturday.

Her research began with three clues about autism: it tended to run in families, children with rubella had a high rate of autistic symptoms and children exposed prenatally to the drug thalidomide, show symptoms, as well.

Irva Hertz-Picciotto, professor of public health sciences at the University of California — Davis, will present "Environment and Autism: Past Evidence, Current Research and Future Quandaries" at 2:15 pm on Saturday.

Irva Hertz-Picciotto, professor of public health sciences at the University of California — Davis, will present “Environment and Autism: Past Evidence, Current Research and Future Quandaries” at 2:15 pm on Saturday.

“This is a controversial topic, but also an important one to learn more about given how many people’s lives are touched by autism,” Shenk said. “Dr. Hertz-Picciotto’s research and outreach work are very widely respected.”

Hertz-Picciotto, an environmental epidemiologist and professor of public health sciences at UC Davis, will highlight epigenetic studies being conducted, and key gaps, persistent myths and enigmas that still need to be solved during her talk on Saturday.

Bale and Hertz-Picciotto join many other speakers as part of this year’s LSSP Epigenetic Revolution Symposium.

The symposium begins Friday, March 13, with talks and presentations extending through March 15. Affiliated events will be going on the entire weekend, extending through March 17.


For a complete calendar of events, visit the Life Sciences and Society Program Epigenetic Revolution event page.

Introducing the 11th Annual LSSP topic: The Epigenetic Revolution

Screen Shot 2015-03-05 at 3.32.13 PM

To introduce our 11th Annual Life Sciences and Society Program, The Epigenetics Revolution: Nature, Nurture and What Lies Ahead that runs at the University of Missouri March 13-15, we figured it would be nice to define the term epigenetics. Spoiler: It’s amazing and it could change everything.

According to Merriam-Webster Dictionary, epigenetics is “the study of heritable changes in gene function that do not involve changes in the DNA sequence.”


Let’s break that down. 

We can inherit something that changes what our genes do, but don’t actually change the code of our DNA.

So what sort of things do genes do?

It might be easier to think about it like this: Genes are like ingredients that make up a recipe which concocts a specific function. Each individual ingredient adds to the bigger picture. Say the recipe is our height. There are many, many genes involved in myself standing at 5 feet 6 inches and my sister towering over me at 5 feet 10 inches.

Though it’s not epigenetics that makes my sister taller than me, epigenetics could help help explain why identical twins exposed to different conditions over their lifetimes, may eventually produce offspring with extreme differences in height, as just one example.

Yesterday, Jack C. Schultz, director of the Christopher S. Bond Life Sciences Center, explained epigenetics to me this way:

“We are not simply the sum of the genes we have, but rather which ones are on or off,” Schultz said. “Those differences in gene activity explain why even identical twins are not totally identical.”

Mary Shenk, the director of this year’s LSSP symposium, said epigenetics is a revolutionary area of research that changes the way we think about genetic effects. Epigenetics research makes it clear that many aspects of the environment—including the social environment—can affect how genes are expressed, she said.

“We have always known that some traits—height, for instance—were strongly influenced by the environment through diet,” Shenk said. “But new research makes it clear just how many ‘genetic’ traits are subject to either environmental influences and/or other influences such as the sex of the parent a gene is inherited from.”

“This is a real game-changer in terms of how we see the world of genes, and makes notions of simple genetic determinism of complex traits increasingly unrealistic,” Shenk added.

The key to understanding epigenetics, is to consider the capabilities of the environment to “switch on or off” the expression of our genes.

Let’s reflect on something you may have (or haven’t) heard about: “Hogerwinter,” more well known as the Dutch Hunger Winter.  The historic famine from the winter of 1944 to the spring of 1945, has been the focal point in some of the most infamous epigenetic research.

Investigators wanted to know if prolonged famine conditions could have an effect on the offspring of pregnant mothers during that time.

“The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance,” by Nessa Carey published by Columbia University Press in 2012, makes a compelling argument about the famine effect on gene expression in subsequent generations.

The research looked at children who were in the second trimester of their mother’s pregnancy during the winter of 1944-1945, and they found an increased incidence of schizophrenia in those children.

Carey’s research suggests epigenetics could explain effects of famine, on the expression of certain genes of the offspring of mothers pregnant during that time.


Illustration by Paige Blankenbuehler/Bond Life Sciences Center

Epigenetics are the nucleus of the 11th Annual Life Sciences and Society Program held at the University of Missouri next weekend, March 13-15. The field has the potential to unlock some of our longest standing questions about who we are and why we are this way, scientists say. The event is a great opportunity to learn more about “The Epigenetics Revolution.”

Schultz says the field of epigenetics is exploding, and it’s important to us for three big reasons.

  • One: Epigenetics helps us understand how we – or any organism – can cope with changing conditions even though we can’t change our genetic makeup.

  • Two: Epigenetics explains how traits can be passed from parent to offspring without changing genetic makeup.

  • Three: Many human diseases, including cancer, seem to involve epigenetic activity. Experiences of the parents, or of developing embryos in the womb could be responsible for difficult-to-understand problems in the offspring, such as cognitive disorders including autism spectrum disorders.

“Discovering how epigenetics works is like discovering an entirely new language,” Schultz said. “That language links our experiences – even emotional ones – to the way we are and the way our offspring look and behave.”

Schultz said exploring those links can help us understand how our environment shapes us and our societies.

According to Shenk, director of the Life Sciences and Society Program, the nine speakers coming to the MU campus all bring their own expertise to epigenetics.  As far as picking a speaker, Shenk said it’s hard to choose just one.

Nonetheless, here are a few to keep on your radar, according to Shenk:

“I am especially looking forward to hearing Annie Murphy Paul talk about her experiences writing about maternal effects for a general audience.

“Tracy Bale and Oliver Rando discuss their work on paternal effects in mice (most recent focuses on mothers instead of fathers so this is especially interesting).

“I am also excited to hear Ted Koditschek from Mizzou discuss the history of the classic Lamarckian idea of the “inheritance of acquired characteristics” and how it relates to findings from modern epigenetics,” Shenk said.

Schedule of events

The location of all speakers and affiliated events will be announced at or on the Life Sciences and Society Program — University of Missouri Facebook page.


6:30 p.m. — Topic of the talk: Sharing epigenetic research with the public. Speaker: Annie Murphy Paul, science writer and author of Origins: How the Nine Months Before Birth Shape the Rest of Our Lives. 


9 a.m. — Topic of the talk: Stress Parents: Maternal and paternal epigenetic programming of the developing brain. Speaker: Tracy Bale, professor of neuroscience and animal biology at the University of Pennsylvania.

10:30 a.m. — Topic of the talk: You are what your father ate. Speaker: Oliver Rando, professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical School.

11:30 a.m. — Topic of the talk: Epigenetic inheritance and evolutionary theory: the resurgence of natural philosophy. Speaker: Massimo Pigliucci, professor of philosophy at the City University of New York.

2:15 p.m. — Topic of the talk: Environment and Autism: Past evidence, current research and future quandaries. Speaker: Irva Hetz-Picciotto, professor of public health sciences at UC Davis.

3:15 p.m. — Topic of the talk: Prenatal stress modifies the impact of phthalates on boys’ reproductive tract development. Speaker: Shanna Swan, professor of preventative medicine at Mount Sinai School of Medicine.

4:30 p.m. — Panel Session with all Saturday speakers.


9 a.m. — Topic of the talk: DOHaD, epigenetics and cancer. Speaker: Suh-mei Ho, director of the University of Cincinnati Cancer Center, and chair of the department of environmental health.

10:30 a.m. — Topic of the talk: The epigenetics of pediatric cancers. Speaker: Joya Chandra, associate professor of pediatrics at the University of Texas MD Anderson Cancer Center.

11:30 a.m. — Topic of the talk: Before epigenetics: Early ideas about the inheritance of acquired characteristics. Speaker: Ted Koditschek, professor of history at the University of Missouri.

Affiliated events: 

Exhibit running March 5-30 at the Ellis Library Collonnade. Exhibit: Generations: Reproduction, heredity and epigenetics.

1 p.m. March 9, at the Ellis Library Government Documents Section. Topic of the talk: Genes, culture and evolution. Speaker: Karthik Panchanathan, department of anthropology, University of Missouri.

3:30 o.m. March 17, at Jesse Wrench Auditorium. Topic of the talk: Profound global institutional deprivation: the example of the English and Romanian adoptee study. Speaker: Sir Michael Rutter, professor of developmental psychology at the Institute of Psychiatry at King’s College in London.

Harm and response

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Bond LSC’s Jack Schultz and Heidi Appel hold model Arabidopsis plants used in many of their experiments. Roger Meissen/Bond LSC

We often think of damage on a surface level.

But for plants, much of the important response to an insect bite takes place out of sight. Over minutes and hours, particular plant genes are turned on and off to fight back, translating into changes in its defenses.

In one of the broadest studies of its kind, scientists at the University of Missouri Bond Life Sciences Center recently looked at all plant genes and their response to the enemy.

“There are 28,000 genes in the plant, and we detected 2,778 genes responding, depending on the type of insect,” said Jack Schultz, Bond LSC director and study co-author. “Imagine you only look at a few of these genes, you get a very limited picture and possibly one that doesn’t represent what’s going on at all. This is by far the most comprehensive study of its type, allowing scientists to draw conclusions and get it right.”

Their results showed that the model Arabidopsis plant recognizes and responds differently to four insect species. The insects cause changes on a transcriptional level, triggering proteins that switch on and off plant genes to help defend against more attacks.

The difference in the insect

“It was no surprise that the plant responded differently to having its leaves chewed by a caterpillar or pierced by an aphid’s needle-like mouthparts,” said Heidi Appel, Bond LSC Investigator and lead author of the study. “But we were amazed that the plant responded so differently to insects that feed in the same way.”

Plants fed on by caterpillars – cabbage butterfly and beet armyworms – shared less than a quarter of their changes in gene expression. Likewise, plants fed on by the two species of aphids shared less than 10 percent of their changes in gene expression.


These Venn diagrams show the number of genes expressed due to each treatment and their overlap. Upward pointing arrows indicate upregulated genes, downward pointing arrows indicate downregulated genes. For example, beet armyworm (S. exigua) shared 21 percent of upregulated genes expressed with cabbage butterfly caterpillar (P. rapae). M. persicae and B. brevicoryne are the two types of aphids compared in the study. Courtesy of Heidi Appel

The plant responses to caterpillars were also very different than the plant response to mechanical wounding, sharing only about 10 percent of their gene expression changes. The overlap in plant gene responses between caterpillar and aphid treatments was also only 10 percent.

“The important thing is plants can tell the insects apart and respond in significantly different ways,” Schultz said. “And that’s more than most people give plants credit for.”

A sister study explored this phenomena further, led by former MU doctoral student Erin Rehrig.

It showed feeding of both caterpillars increased jasmonate and ethylene – well-known plant hormones that mediate defense responses. However, plants responded quicker and more strongly when fed on by the beet armyworm than by the cabbage butterfly caterpillar in most cases, indicating again that the plant can tell the two caterpillars apart.

The result is that the plant turns defense genes on earlier for beet armyworm.

In ecological terms, a quick defense response means the caterpillar won’t hang around very long and will move on to a different meal source.

More questions

A study this large has potential to open up a world of questions begging for answers.

“Among the genes changed when insects bite are ones that regulate processes like root growth, water use and other ecologically significant process that plants carefully monitor and control,” Schultz said. “Questions about the cost to the plant if the insect continues to eat would be an interesting follow-up study for doctoral students to explore these deeper genetic interactions.”

Frontiers in Plant Science published the primary study in its November 2014 issue. The sister study can be read here.


Big discoveries come in little (capsid) packages

Adeno-associated virus type 2 at 3.0 A (xie, et al, Proc Natl Acad Sci U S A. 2002; 99:10405-10.) Courtesy David Pintel

It’s an understatement to say viruses are small.

But an average virus dwarfs the diminutive variety known as parvoviruses, which are among the most minuscule pathogens known to science.

Tucked inside a protective protein shell, or capsid, parvoviruses contain a single DNA strand of about 5,000 nucleotides. If parvo’s genetic material is like an hour-long stroll around your neighborhood, a bigger virus like herpes is equivalent to walking from St. Louis to Columbia, Missouri.

Dr. Dave Pintel stands next to a scan in his lab in Bond Life Sciences Center on Tuesday, Feb. 3, 2015.

Dr. David Pintel stands next to a scan in his lab in Bond Life Sciences Center on Tuesday, Feb. 3, 2015. Hannah Baldwin/Bond LSC.

“I joke that we can do the whole parvovirus genome project in an afternoon, because it’s just taking it downstairs and having it sequenced,” said David Pintel, a Bond Life Sciences Center virologist and Dr. R. Phillip and Diane Acuff endowed professor in medical research at the University of Missouri. “It’s the size of one gene in the mammalian chromosome.”

But that little stretch of DNA still has plenty of tricks up its sleeve.

Pintel has spent nearly 35 years studying parvo and is one of the world’s foremost experts on the virus, but he’s still plumbing the tiny pathogen’s depths.

His lab focuses on unraveling how parvo interferes with a host cell’s lifecycle and understanding the virus’ quirky RNA processing strategies.

“Even though the virus is small, it’s not simple,” David Pintel said. “Otherwise we’d be out of business.”

Over the last two decades, parvo has become an important tool for gene therapy, an experimental technique that fights a disease by inactivating or replacing the genes that cause it. Researchers enlist a kind of parvovirus known as adeno-associated virus as a gene therapy vector, the vehicle that delivers a new gene to a cell’s nucleus. Pintel helped suss out the virus’ basic biology, an important step for developing effective gene therapy.

A varied virus

The name ‘parvo’ comes from the Latin word for ‘small.’ But the virus’ size makes it a resourceful, versatile enemy and a valuable model for understanding viruses and how they interact with hosts.

Parvoviruses fall into five main groups. They infect a broad swath of animal species from mammals such as humans and mice to invertebrates such as insects, crabs and shrimp.

Canine Parvovirus at 2.9 A (Tsao, et al, Science. 1991; 251:1456-65.) Courtesy David Pintel.

Canine parvovirus, or CPV, is perhaps the best-known type.

It targets the rapidly dividing cells in a dog’s gastrointestinal tract and causes lethargy, vomiting, extreme diarrhea and sometimes death. In humans, Fifth disease, caused by parvovirus B19, is the most common. This relatively innocuous virus usually infects children and causes cold-like symptoms followed by a “slapped cheek” rash. There is no vaccine for Fifth disease, but infections typically resolve without intervention.


Reading the transcript

Pintel surveyed the whole parvo family to understand its idiosyncrasies.

To study bocavirus – a kind of parvo recently linked to a human disease – Pintel looked closely at the dog version, minute virus of canines (MVC). MCV serves as a good model for the human disease-causing virus. While examining MVC, he noticed an unexpected signal in the center of the viral genome. The signal terminates RNA encoding proteins for the virus’ shell, a vital part of the pathogen.

Finding such a misplaced signal in the middle of a stretch of RNA is like coming across a paragraph break in the middle of a sentence.

Pintel knew the virus bypassed this stop sign somehow, because the blueprint for the viral capsid lies further down the genome.

To overcome this stop sign, this particular parvovirus makes a protein found in no other virus. The protein performs double-duty for the virus: It suppresses the internal termination signal and splices together two introns, or segments of RNA that do not directly code information but whose removal is necessary for protein production. Splicing the introns together ensures that the gene responsible for producing the viral capsid is interpreted correctly.


Viruses and hosts: a game of cat and mouse

The conflict between a virus and a host is a constantly escalating battle of assault and deception.

Viruses need a host cell’s infrastructure to replicate, but have to fool or outmaneuver its defenses.

Pintel discovered one example of this trickery in mice, where parvo triggers a cellular onslaught known as the DNA damage response, or DDR. This type of parvo co-opts that defense. Normally DDR pauses the cell cycle to keep damaged DNA from being passed on to the next generation of cells, but parvo exploits that delay, buying time for the virus to multiply.

“For many, many hours the cells are just held there by the virus while the virus continues to replicate,” Pintel said. “And then that cell never survives; the virus kills the cell. It’s that holding of the cell cycle — which is part of the DNA damage response — that the virus hijacks to hold the cell cycle. It’s really cool.”

Parvo’s small size makes it especially beholden to their hosts. But that can make them particularly revelatory for researchers.

Parvovirus samples from an experiment labeled by Femi Fasina, a postdoc in Pintel's lab.

Parvovirus samples from an experiment labeled by Femi Fasina, a postdoc in Pintel’s lab. Caleb O’Brien/Bond LSC.

“It’s a twofold thing,” Pintel said, “Because it’s a virus that’s dependent on the cell, when you learn how the virus is doing these things, you learn how the cell does those basic processes. If we’re looking at a viral-cell interaction, yes, we’re looking at it from a viral point of view, but on the other hand we’re trying to understand the basic cellular process.”

Uncovering such nuanced interactions is a painstaking, laborious process that often goes unheralded by mass media. But those fundamental discoveries provide the building blocks upon which other researchers depend, said Femi Fasina, a postdoc in Pintel’s lab.

“When you understand basic biology, people can walk on those advancements. Although we don’t see the impact immediately, such things lead to breakthroughs that will revolutionize a lot of things.”


A small question

Despite his deepening understanding of how parvo works, there remains one debate about the virus that Pintel deems beyond the scope of his research: Are the tiny slivers of DNA that comprise parvoviruses even alive?

“I think that’s a crazy question,” he said. “It’s semantics. The virus is a genome. It goes into a cell, it doesn’t do anything until it’s inside of a cell and then it does stuff.” So whether you write parvoviruses into the book of life depends entirely on how you define the word ‘alive.’

“I put that in the realm of philosophy,” Pintel said, “not the realm of science.”

2015 Graduate Life Sciences Joint Recruitment Weekend highlights collaborative nature of research at Bond Life Sciences Center

Faculty and students crowded the hallways at Bond Life Sciences Center for an interdisciplinary poster session on Saturday. About 40 prospective graduate students listened to faculty and current graduate students from the biochemistry, interdisciplinary plant group, plant sciences, molecular pathogenesis and therapeutics (MPT), genetics area program and the life sciences fellowship program discuss their work.
The poster session was part of the 2015 Graduate Life Sciences Joint Recruitment Weekend, an event aimed at helping prospective graduate students determine if MU is the right place for them to continue their education. About 175 people participated, including current graduate students and faculty.
MU biochemistry senior Flore N’guessan said she applied to the MPT program because of her interest in virology.
“I’ve always wanted to do research,” she said.
N’guessan is currently a researcher in the Burke lab, which works on testing potential antiviral therapeutics on HIV. N’guessan has applied to other graduate programs but said that the interdisciplinary and collaborative nature of MU’s life sciences program appeals to her because it allows her to gain skills from other labs.
“It’s a collaborative and interdisciplinary university,” Dr. Jay Thelen, an associate professor of biochemistry, said. “That’s what this weekend highlights.”
Thelen emphasized that the benefit of events like the interdisciplinary poster session allows prospective students to see the diversity of science studied at Bond LSC and in labs throughout MU. And, he said, “It’s exciting to see how many students there are.”
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Parkinson’s “trash pick-up problem”

Protein Specimen

Protein specimens are prepared here in a Bond Life Sciences lab. Bond LSC’s Mark Hannink recently identified a protein pathway could be useful in restoring mitochondrial recycling in certain cells, a problem that leads to familial Parkinson’s Disease.

It’s as if your recycling man quit his job and never came back.

Bags pile up to unexpected heights as waste continues to be generated and brought out to the curb. Day after day, the waste builds up as no one comes to pick them up.

For individuals with Parkinson’s disease, an accumulation of waste causes specific brain cells to die. The result is the onset of the disease.

But, instead of aluminum cans, plastics and paper, the waste that builds up in the brain cells of individuals with Parkinson’s is damaged mitochondria. Mitochondria are the cellular components that generate energy needed to keep cells alive.

When mitochondria is damaged and is no longer capable of making energy, it must be sent to the recycling center of a cell (called the lysosome).

Mark Hannink, a scientist at the Bond Life Sciences Center and professor of biochemistry at the University of Missouri, is peeling away the layers of this onion, one at a time.

His new research on a novel protein called PGAM5 (phosphoglycerate mutase family member 5) is pointing the way to finding a drug that can treat the disease.


Mitochondria suffer “wear and tear,” just like old cars

Mitochondria are endlessly helpful to a cell.

These powerhouses produce energy for a cell, control the cell division cycle and help regulate synapses. However, the mitochondrial proteins that produce energy eventually become damaged and no longer function properly.

“That’s part of the normal life cycle of mitochondria,” Hannink said. “Just like when the motor in an old car gives out due to wear and tear, that motor needs to be taken out and sent to the scrap dealer to be recycled and a new motor needs to be put in the car to keep it running.”

When mitochondria wear out they need to be sent to “recycling.”

“If that recycling pathway doesn’t work, the defective mitochondria will build up and will disrupt cell physiology, ultimately causing that cell to die” Hannink said.

Parkinson’s Disease is the clearest example of this recycling failure.

In early onset Parkinson’s, mutated proteins “forget” to take damaged mitochondria to the recycling center, resulting in build-up of toxic waste and, eventually, early onset of the disease.

“If the recycling mechanism isn’t functioning properly, those neurons die,” Hannink said.


Mark Hannink, lead investigator of the study, sits in his lab at the MU Bond Life Sciences Center. | Photo by Paige Blankenbuehler

Mark Hannink, lead investigator of the study, sits in his lab at the MU Bond Life Sciences Center. | Photo by Paige Blankenbuehler

Peptides behave like drug molecules

Hannink recently published research on the PGAM5 pathway in the Journal of Biological Chemistry along with MU graduate students Jordan M. Wilkins and Cyrus McConnell and fellow Biochemistry faculty member, Peter Tipton.

While its basic nature hides it from the view from the general public, this research takes a large step in the science of Parkinson’s disease.

Beyond defining the regulation of a pathway largely unstudied, their work discovered that a peptide regulates the pathway. Importantly, this peptide is able to alter the activity of the PGAM5 protein and stimulate an alternative recycling pathway for mitochondria.

Peptides are a clear signpost on a path toward drug development.

“Any time you can identify a biological process that is regulated by a peptide, that peptide becomes a lead candidate in the search for small, drug-like molecules that will act the same way,” Hannink said.

For Parkinson’s Disease, the goal is to find ways to repair the mitochondria recycling process.

“We propose that, by regulating PGAM5, it may be possible to restore mitochondrial quality control to dopaminergic neurons of patients with Parkinson’s and lessen the severity of the disease,” Hannink said.


What’s next?

While Hannink’s findings are exciting, there are also nuances to consider.

His research focuses on familial Parkinson’s disease, and it remains unknown whether sporadic Parkinson’s is also due to a defective mitochondrial recycling pathway. Sporadic Parkinson’s accounts for the vast majority of cases and typically affects older people.

It’s not clear if the PGAM5 pathway is also defective in those cases, Hannink said.

The next step of his research is to identify a small molecule that can regulate the PGAM5 protein in cells, just as the peptide did in his test-tube experiments.

Hannink thinks that development of a drug based on the PGAM5 pathway could be useful in restoring mitochondrial recycling in certain cells – like neurons affected in Parkinson’s – while blocking this recycling pathway in other cells, — like cancer cells.

The idea also needs to be tested using mice as a model system. The goal of those experiments will be to determine if the PGAM5 protein can stimulate alternative recycling pathways that can clean up and recycle damaged mitochondria pathway in neurons of mice.