Bond Life Sciences Center’s Ron Mittler was recently named Curators’ Distinguished Professor by the University of Missouri System Board of Curators.
This top honor is bestowed on professors for outstanding scholarship who have established substantial reputations within their field.
“I am honored. Mizzou is such an amazing, supportive, and collaborative research environment and I feel lucky being here,” Mittler said. “I enjoy every moment working at Bond LSC.”
Mittler’s research substantially focuses on the role reactive oxygen species (ROS) play in the regulation of different biological processes. While ROS can be destructive within cells, he discovered it also plays a role in how plants systemically respond to environmental threats. He is a nationally recognized expert in this field of study.
“My work covers many biological systems and organisms with a focus on how they respond to stress and the role of ROS in their responses,” Mittler said. “I also study how organisms respond to a combination of different stresses, a problem that we are already facing in nature and in field environments that will get worse due to global warming and climate change.”
Mittler came to Mizzou in 2018 from the University of North Texas. Now a Bond LSC principal investigator and professor of plant sciences in the College of Agriculture, Food and Natural Resources, he joins eight other current and former Bond LSC principal investigators who received this honor in previous years.
“Dr. Mittler’s path-breaking research on cell signaling by reactive oxygen species and its role in how organisms cope with stress combinations is a nice example of cross-disciplinary research in Bond LSC on contemporary problems that require life sciences solutions, Bond LSC Director Walter Gassmann said. “That his insights have relevance also for cancer research in humans supports Bond LSC’s concept of bringing researchers from different disciplines together. Ron is exceedingly deserving of the Curators’ Distinguished Professorship and is a fitting example of the research excellence the Bond LSC strives to enable and stimulate.”
Individuals are nominated for this honor based on performance, service and their teaching record, and the title can be renewed every five years.
Visit Show Me Mizzou to see all of the Mizzou faculty members who received distinguished professor honors at the Sept. 7 Board of Curators meeting. Previously named Curators’ Distinguished Professors at Bond LSC include Chris Lorson, Dong Xu, Gary Stacey, Chris Pires, David Pintel, John Walker, Gary Weisman and Michael Roberts.
If the world can be taxing on a person as pressure mounts, just think about how stress must feel to plants.
Humans can add a layer of clothing when cold or get a glass of water when thirsty, but plants do not share this simple luxury and must endure whatever environment they sprout in.
As climate change, pollutants, and extreme weather patterns escalate, this poses a serious global threat to plants and our food supply.
Ron Mittler, a principal researcher at the Bond Life Sciences at the University of Missouri, recently looked at how this piling up of multiple stressors at once can significantly decrease plant survival.
“The principle is that you can have a combination of several different stressors, each by itself has no effect on the plant but when they come together, they’re causing severe effects,” Mittler said.
Studying plant response to stress isn’t a new thing, but Mittler’s focus on the compounded effects of stressors may give us a better idea of the threshold of stress plants can endure in our changing climate. Multifactorial stressors combine three or more stress factors simultaneously impacting plants. Four categories of stress— biotic, climate, anthropogenic, and soil threats — all become worse as climate change and environmental pollution progress, subsequently decreasing plant quality of life.
Biotic threats relate to enemies like pathogenic bacteria and insects. Similarly, soil threats are determined by poor nutrient soil and salinity. Climate threats include extreme temperatures and drought. Anthropogenic threats are man-made as humans use harmful pesticides and create microplastics.
Arabidopsis thaliana seedlings, a model plant used in experiments, were placed side by side on a plate and received a combination of stress conditions such as heat, salt, excess light, acidity, heavy metal, and oxidative stress. Researchers studied the growth, survival, and molecular responses of the seeds. Seedlings were grown on plates rather than in soil to isolate and study the impact of multifactorial stress.
Seedlings grew on separate plates and experienced different individual or combined stresses. Results showed that each individual stressor applied to the seedling had a minimal effect on the plants but with the increase in the complexity and number of stress factors affecting the plants, survival, root growth, and chlorophyll content declined. Similar results were also found for seedlings grown in soil.
Ecosystems are already seeing these impacts in Florida and Germany. Multifactorial stress of heat and pollution prompted algae blooms to grow exponentially. This toxic overgrowth led to thousands of manatees dying. Entire forests in Germany are experiencing massive storms followed by long periods of drought, insect attacks, and fires.
Mittler said things may not look dire now, but we will eventually reach a point of no return where plants die off in mass quantities or even go extinct.
“The harmful effects of stress on the nation can serve as a dire warning for society. We may not see the effects now but 10, 20, 40 years down the road we will be having severe problems with our food chain,” Mittler said.
Since there are multiple factors at stake, predicting negative impacts on agriculture and ecosystems is tricky as researchers are unsure how this domino effect may unravel. What they do know for certain is that there will be severe consequences and we are already seeing them today.
These sporadic weather extremes are weakening the plants, making them more vulnerable to insect predators and other stressors.
The research yielded alarming results, and Mittler highlights that this is a dire problem that people need to take seriously. Once people understand the severity of this problem, he hopes individuals and policymakers will take action before the consequences become irreversible.
The Mittler lab is working on several fronts to address this problem and is trying to find a solution to it. They are currently studying multifactorial stress combination in different crop species, such as soybean, rice, and tomato. In addition, also identifying key plant regulators that are activated during multifactorial stress combination. These will be used in future breeding efforts to increase the tolerance of different crops to multiple stresses.
This study is now an international collaboration between the Mittler and Zandalinas laboratories, as Dr. Sara Zandalinas took on a faculty position in Spain.
“His mentoring style really fit with what I needed going forward,” Thomas said. “In medicine you can help hundreds of people, but with science and research you can help millions of people as long as that science is translatable.”
Thomas spent his first rotation as a medical student in the lab of the Bond Life Sciences Center scientist and professor of Molecular Microbiology & Immunology and instantly enjoyed it. Typically, medical students go through three ten-week rotations but Thomas only needed one. He quickly enjoyed the work and saw opportunities with the research in the lab.
“In my rotation last summer I really enjoyed the lab, it was a great environment,” Thomas said. “It was a really inviting environment to work in and now we get to do some really cool science.”
Thomas studies cancer immunomodulation through aptamer technology in the Burke lab. Aptamers are small DNA or RNA nucleic acids that can bind to different molecular targets, similar to puzzle pieces.
“We have an aptamer that targets immune cells and an aptamer that targets cancer cells,” Thomas said. “We’re looking at bringing those two cells together in close proximity and activating our immune cells to kill cancer cells.”
Cancer immunomodulation is a different approach to fighting cancer, where instead of using drugs to destroy cancer cells in chemotherapy, the body is encouraged to induce anti-tumor immune responses.
Finding a lab environment where Thomas could focus on cancer was incredibly important to him when choosing where he would complete his research. He wants to focus on pediatric hemotology-oncology, the combined study of blood and cancer.
Thomas began his time at the University of Missouri as an undergraduate majoring in biochemistry and spent many hours researching and completing homework in chemistry labs.
But, that’s not what sparked his passion to pursue the eight year program to become a physician-scientist with an MD-PhD. His biochemistry degree first landed him a job at Washington University in St. Louis studying novel cell death pathways in a research lab.
Through this research, Thomas used C. elegans, a transparent roundworm, to study human disease. Many of the genes in the roundworm are homologous to human genes, making them useful to study a broad range of human diseases such as neurological disorders, heart disease and kidney disease.
“That’s really where I fell in love with science,” Thomas said. “Especially the clinical translation of science, so from bench to bedside. Thankfully I had a really great mentor there that drove me to pursue my MD-Ph.D.”
These mentors impacted Thomas in various ways throughout his position at Washington University. Gary Silverman, M.D., Ph.D., is the Chairman of the Department of Pediatrics at the Washington University School of Medicine. During live meetings Silverman was one of the people Thomas would present the data they discovered and receive feedback from.
An additional mentor for Thomas was his primary investigator, Cliff Luke, Ph.D. whom Thomas worked directly for. Luke is an associate professor of pediatrics and newborn medicine at Washington University. It was Luke that helped Thomas find his love for science and joy in the meticulous work of research.
“They taught me a lot of lab techniques but more importantly about the joy for data,” Brian Thomas, MD-PhD candidate, said. “They also taught me the joy for failing and getting back up from failure and just how important that is.”
Thomas returned to the University of Missouri to pursue his combination MD-Ph.D.
“I know we had good science going on here from when I was an undergraduate,” Thomas said. “I truly believe when choosing a lab to do your graduate coursework is that it’s important to find a good mentor. It doesn’t really matter the science you’re doing as long as you have a mentor who can teach you how to do good science, well-controlled science and really how to think like a scientist.”
His expected graduation from the dual degree program isn’t until 2027 or 2028, but that hasn’t stopped Thomas from thinking about where he can make the biggest impact, whether that be returning to Washington University for his residency program or being exposed to a different clinical environment outside of Missouri.
Saathvik Kannan, Kamal Singh, and Austin Spratt, worked together at Bond LSC to identify new SARS-CoV-2 variants. | photo by Davis Suppes, Bond LSC
By Davis Suppes | Bond LSC
Variants of the virus that causes COVID-19 continue to plague the world with spikes in infection, keeping the current pandemic from being fully controlled as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections remain unmanageable in some parts of the world.
Researchers at Bond Life Sciences Center and the University of Nebraska Medical Center (UNMC) have been conducting research on mutations in four new variants, B.1.1.7, B.1.351, P.1 and CAL.20C. These evolving variants appear to be more infectious and transmissible than the original Wuhan-Hu-1 virus.
It all started with a new spike in infections of a variant of SARS-CoV-2 in the UK. Despite a slowdown in infections due to precautions of masks and lockdowns, the new spike meant something about the virus had changed.
“Our goal was to find out where these variants are distributed, and how they are migrating,” said Kamal Singh, Assistant Director Molecular Interactions Core, and scientist at Bond LSC. Singh was a corresponding author on the paper and has been at Bond LSC for 12 years.
Their work showed completely different mutations in these variants based on regions, but also where variants have common lineage. That commonality can be seen between the CAL.20C and B.1.351 variants.
While related to each other, they also developed different mutations.
“B.1.1.7 was more infectious and was able to spread to more people. It slowly dominated and that’s what happened in the United States as B.1.1.7 is now the dominant variant of SARS-CoV-2 in the US,” said Saathvik Kannan, a co-author. Kannan is going to be a 10th grader at Columbia’s Hickman High School this fall but works under Singh at Bond LSC as a computer programmer and researcher.
Once they identified the related COVID-19 variants, they wanted to trace their migration. This allows them to see where the mutations are being carried and which regions have a more dense number of infections. The prevalence of variants was key in identifying where they were moving.
Their analysis looked at certain mutations in each variant to see how they were related, why some sequences have mutations that others don’t and tried to determine how they evolved from their original sequence.
By comparing the structure of each virus, they were able to illustrate how the related mutations moved state by state across the country.
This Sankey diagram for variant CAL.20C in the United States.They aligned the first-known CAL.20C sequences from each state then grouped the sequences based upon the date collected and closely their structures matched, with cut-offs of 96, 94, 93, 92, 91 and 90 percent compared with the previous group.
“It is pretty clear that some states have a higher homology match, which helps us see a pretty linear trend of migration from the Western states to the East in the United States,” said Austin Spratt, a computer science senior and lead author on the paper. Spratt has worked under Singh at Bond LSC for two years.
The study cautions that the sequences of viruses are being deposited at an unprecedented rate, so it is possible that some conclusions may change as more sequences of variants become available.
“These variants are continuously evolving and complex in nature, but a proper understanding of what makes each variant unique, its genetic makeup and its interaction with host proteins is critical to developing the most effective vaccine,” said co-corresponding author Siddappa Byrareddy, Professor & Vice-Chair of Research, in the Department of Pharmacology & Experimental Neuroscience, at the University of Nebraska Medical Center. “Not only will this help us to design better vaccines now, but greatly help us to be prepared to deal with more mutant variants in the future.”
Although analysis indicates that mutations only in one variant do not reflect evolution of it, these genetic mistakes may increase infectiousness of a particular variant
The short period of time, volume of variants and limited travel around the world all point to a greater infectivity than the original (Wuhan-Hu-1) virus. Recent deadly surges in India caused by variant B.1.617.2 or the Delta variant will soon be added to their analysis to further understand the COVID-19 pandemic.
Their research was published in the paper ‘Evolution, Correlation, Structural Impact and Dynamics of Emerging SARS-CoV-2 Variants’ in the “Computational and Structural Biotechnology Journal” on June 19, 2021.
Funding provided by: Bond LSC, Swedish research Council, American Lung Association, National Institute of Dental and Craniofacial Research in collaboration with Prof. Gary Weisman of the Bond Life Sciences center.
Although Brassica cretica doesn’t look much like cabbage, broccoli or kohlrabi, the wild relative is the closest relation to our modern vegetables and its endurance might show us how to make our vegetable crops more resilient in the future. | Illustration courtesy of Andi Kur
By Roger Meissen | Bond LSC
You might not envision plant scientists as the modern-day Indiana Jones of biology, but University of Missouri researchers have been hot on the hunt for an evolutionary history, looking for clues to the ancestors of our gardens and grocery shelves.
To find the closest wild relative of the wide-ranging plant species Brassica oleracea, Makenzie Mabry and the Chris Pires lab figuratively combed the hills and seashores of Europe, Africa and the Mediterranean to find a long-lost cousin to many of our vegetable staples.
What they found brings together a puzzling past of a species that could provide insight for conservation and breeding efforts for the future of our vegetables.
Makenzie Mabry
“These wild relatives — because they are not under cultivation like our crops — have adapted differently and might be better at herbivory defenses or might be more drought tolerant, and knowing where things were domesticated may help identify genes for those traits,” said Mabry, a principal author and recent Mizzou doctoral graduate. “With techniques like CRISPR, we can look at these differences among wild relatives once they’ve been identified using family trees, and then in the future, hopefully, breeders can then move those traits into the plants, which could help our crops dealing with future climate change.”
The Family Bush
The family structure for mustards to cabbages and everything in between is a messy one.
Chris Pires
“Charles Darwin really plugged for evolution to be thought of as a tree with branching patterns, but he did say, well, you know, in some cases, maybe it’s really more like a coral or a shrub,” said Pires, principal investigator and co-investigator on this project. “It’s like the branches are all mixed together, and this paper is revealing Brassica as a classic case of this, a very shrubby ancestry. It’s a mess.”
Whether it’s a bush or a coral, the tangle of Brassica oleracea species show a full gambit of diversification.
You have versions of the species that evolved their leaves into staples like cabbage or kale, others where flowers or inflorescences were domesticated into what we eat now as broccoli or cauliflower and even more that put their efforts into underground parts like kohlrabi.
Pires likens this to how modern dogs have diversified into starkly different breeds from Great Dane to chihuahua.
“You got dogs with big heads and ones wagging fluffy tails and others with little-bitty feet, but they are all still the same in that they are all clearly dogs, right?” Pires said. “Just like dogs, Brassica has shown so much plasticity during its domestication, but many still think of each vegetable as distinct branches and that’s obviously not at all what has happened.”
Pinpointing the origin
This path to finding ancestors and relatives of Brassica oleracea requires covering a lot of territory from comparing thousands of genes to scrutinizing ancient texts on cabbage to analyzing trade routes in the Mediterranean Sea.
Recent theories on the origin of Brassica oleracea have ranged from believing there is a single common ancestor to multiple domestication attempts from several ancestors. Despite these hypotheses, it had yet to have been fully confirmed. From England to France to Spain, each region has a certain pride in its favorite varieties of the species. One Greek legend refers to where cabbage sprung from where Zeus’ sweat hit the ground.
The team looked through the literature and archaeological evidence across centuries for these cultural references to gain insight into the origin of the species.
“For some reason, cabbage specifically means a lot to the English, but one of the parts that I think is really cool is that these vegetables have such cultural identities,” Mabry said. “Whether it’s a backyard garden in Portugal or England, there’s a lot of humanity in Brassica oleracea and while understanding that history is complicated, it has such a human component to it that deserves attention.”
The genetics beneath
From a genetic standpoint, Mabry compared 224 different specimens representing 14 crops and nine wild species. After grinding up the leaves in liquid nitrogen and using the Mizzou Genomics Technology Core to sequence transcriptomes (the expressed part of genomes), she then analyzed the DNA from samples that were originally collected all over the world, and then looked for overlapping similarities to understand their shared evolutionary history.
“Just like my mom and I share a set of genes, I can look at the genes in common here. Each sample will have little bits of differences due to mutations, but the more closely related they are the more they share those differences,” Mabry said. “We found Brassica cretica is the closest living wild relative, which grows in the landscape of the eastern Mediterranean region east of Italy. But my favorite part might be we also found that B. cretica has a long history of at least being partially domesticated and then returning to the wild.”
These so-called feral species of former vegetables hold a lot of promise.
“For me, I really love the feral plants. These plants had a different evolutionary history through being cultivated then returning to the wild, now on their own their own path doing their own thing,” Mabry said. “I think it’s really exciting because this subset of plants have even more in common with our crops than wild relatives because they have been domesticated at one time with the same subset of genes. This is under-appreciated gene pool that could really be an exciting avenue for future crop improvement.”
Mabry’s next step is to go in person to these regions in Greece, Crete, Italy, and Morocco to search the hills herself for the ancestors of mustard as part of a National Geographic grant project postponed because of Covid-19.
“I was supposed to go to create and collect these plants in March 2020 and then the pandemic happened, so now that is the next step to figure out,” Mabry said. “My goal is to go next summer once vaccination rollouts around the world play out. We’ll get there soon, and I know the plants will be there waiting.”
Yesterday, Tom Spencer, MU’s interim vice chancellor for research and economic development, officially named Bond LSC Interim Director Walter Gassman to the permanent director role. Below is Spencer’s announcement.
Colleagues,
Today, I am pleased to announce that Walter Gassmann, professor in the Division of Plant Sciences and a member of the Interdisciplinary Plant Group, has agreed to serve as director of the Bond Life Sciences Center (LSC) effective this month.
Walter stepped into the role of interim director at Bond LSC July 1, 2017. Since then, his leadership has guided the center in its mission, and we have appreciated his steady hand as the center and the Office of Research and Economic Development adapted to funding changes. Walter’s stepped-up emphasis on the research enterprise is helping to address our systemwide focus on increasing research and creative endeavors.
Bond LSC’s culture enables 27 faculty investigators from 12 academic units to solve problems in human and animal health, the environment and agriculture. The collaborative, interdisciplinary nature of the work conducted at Bond LSC is a sound model for NextGen Precision Health. Basic and advanced research conducted at the center and the partnerships formed will figure prominently in advancements made in fundamental discovery and translational medicine.
Dr. Gassmann has been an active scientist at the center since its inception, and his collaborative research focuses on the inner workings of the plant immune system, in particular, how it is activated and kept in check to prevent harmful side effects from overactivity. His lab will continue its work as he officially moves into the permanent director role. Read more about Walter and his accomplishments here.
Congratulations, Walter.
Sincerely, Tom Spencer Interim Vice Chancellor for Research and Economic Development
Crops resist bacterial leaf blight; ruling clears path to provide smallholder farmers with a safe, affordable option for preventing destructive disease
A farmer works on paddy rice field.
Columbia and St. Louis, MO, October 14, 2020 – The Healthy Crops team, with support from the Bill & Melinda Gates Foundation, have used gene editing tools to develop new varieties of disease-resistant rice that regulators in the United States and Colombia have determined are equivalent to what could be accomplished with conventional breeding. Bacterial blight can reduce rice yields by up to 70 percent, with the heaviest losses typically experienced by smallholder rice growers in low and middle-income countries. This has a profound impact on farmer productivity and economic mobility. The Healthy Crops team turned to gene editing to develop disease-resistant varieties as a way to provide farmers with a safe, affordable, effective solution.
“We first set about to understand the gene the bacteria use to make the plant vulnerable to its disease,” said Bing Yang, PhD, a researcher with the University of Missouri Bond Life Sciences Center professor, Division of Plant Sciences and member, Donald Danforth Plant Science Center in St. Louis. “We then used our CRISPR technology precisely to remove the element in the gene to avoid the pathway the pathogen takes that makes the plants susceptible to blight.”
Bing Yang is a principal investigator at Bond LSC, a professor in the Division of Plant Sciences and member of the Donald Danforth Plant Science Center in St. Louis. | photo by Roger Meissen, Bond LSC
The team used gene editing to create rice lines in elite varieties that are comparable to naturally occurring variants. These lines can resist infection by bacterial leaf blight, which leads to major losses for one of the world’s most important food crops. The rulings from the United States Department of Agriculture (USDA) and the corresponding authority in Colombia, the Instituto Colombiano Agropecuario (ICA), clear the way for field tests to select the best material for distribution to breeders in the U.S. and Colombia.
The improvements were accomplished via gene editing, which did not introduce any DNA into the plants and focused on “promoter regions” in three genes that are targeted by the causative agent of rice blight, the bacterium Xanthomonas oryzae pathovar oryzae. The research was described in an article in Nature Biotechnology in 2019.
Yang is just one member of the research consortium, headed by Humboldt Professor Wolf B. Frommer from Heinrich Heine University Düsseldorf (HHU), that has worked more than four years on this research. Six research institutions on three continents were involved including the University of Missouri, Donald Danforth Plant Science Center, University of Florida, the Alliance of Bioversity International and the International Center for Tropical Agriculture (CIAT) in Colombia, the Institut de Recherche pour le Développement (IRD) in France and the International Rice Research Institute (IRRI) in the Philippines.
In the wake of the ruling from U.S. and Colombian officials, the new blight-resistant varieties can now be used to introduce the resistance trait into many different types of rice via standard breeding strategies. Additional testing and breeding work is expected to take place in multiple locations that are favorable for growing tropical rice varieties.
“It’s exciting to use science and technology to do to help farmers protect and improve their rice production,” Yang said. “We hope to work closely with the local institutions in the next phase to introduce these into the varieties of rice small farmers use.”
The Healthy Crops Team has no commercial interest in its work. Its goal is to ensure disease- resistant rice varieties are accessible and affordable, especially for smallholder farmers who depend on rice production to support their families.
About The Donald Danforth Plant Science Center
Founded in 1998, the Donald Danforth Plant Science Center is a not-for-profit research institute with a mission to improve the human condition through plant science. Research, education and outreach aim to have impact at the nexus of food security and the environment, and position the St. Louis region as a world center for plant science. The Center’s work is funded through competitive grants from many sources, including the National Institutes of Health, U.S. Department of Energy, National Science Foundation, and the Bill & Melinda Gates Foundation. Follow us on Twitter at @DanforthCenter.
About Bond Life Sciences Center
Founded in 2004, the Christopher S. Bond Life Sciences Center was designed with teamwork in mind, fostering collaborations between scientists of diverse disciplines and backgrounds. From cancer and HIV to plant science and informatics, our researchers work together to move basic science forward and lay the groundwork for a better world. Learn more at bondlsc.missouri.edu.
Jiude Mao works on BPA testing in the lab of Cheryl Rosenfeld.
By Mariah Cox | Bond LSC
Bisphenol A, more commonly known as BPA, has been a source of scientific dispute for the past decade. With a lack of consensus among scientists, consumers are left unaware of the potential harms of the chemicals in plastic.
In response to a recent report by the Food and Drug Administration (FDA) that claims BPA is safe at the current levels occurring in foods, Bond Life Sciences Center principal investigator Cheryl Rosenfeld and a group of researchers across the country have teamed up to release a secondary analysis of the existing data, which disputes this claim.
The industrial chemical is used in manufacture of plastics and resins, and it is commonly found in plastic food containers, water bottles, food can linings and other consumer products. BPA can leach out into water supplies and food where humans and wildlife may be exposed to this ‘persistent chemical’ by ingestion or inhalation.
All of the researchers on the second report were a part of the original team put together by the FDA to study the effects of BPA. However, many researchers on that team disagree with the FDA’s re-analysis and interpretation of their individual findings.
By using the publicly available data published on the National Toxicology Program’s website, these scientists reevaluated the information originally compiled by Rosenfeld and dozens of colleagues as part of a Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA).
Cheryl Rosenfeld had concerns of this Consortium project from the beginning.
“The idea at the outset was that individual investigators and FDA scientists partner together to address the question as to the safety of BPA, but even at the initial meetings, several concerns were raised,” Rosenfeld said.
The major source of disagreement boiled down to lab procedures, statistical analysis and a lack of regard for the inter-related effects of BPA on possibly multiple target organs and bodily functions. Going into it, the researchers had minimal input into the general experimental design, including a rat model that may be less sensitive to the effects of this chemical, the dosages of BPA that were tested, the fact that BPA was administered by what many consider a stressful procedure, oral gavage, and the period of administration.
One problem that was not thoroughly considered is the potential for nonmonotonic effects of BPA. That essentially means BPA shows adverse effects on the body at low and high doses, but not in between or middle-of-the-road doses.
On top of discrepancies over the research procedures, the researchers criticize the FDA for using stringent statistical analysis that may filter out important differences between groups.
“It’s like a metaphor about dropping your keys in a parking lot and looking over by the curb for them because there’s better light there,” said Gail Prins, a professor at the University of Illinois – Chicago and a collaborator on the original and secondary research project. “They’re concluding that BPA is not significant, but they’re not looking in the right places for significant results.”
In statistics, there are type one and type two errors. A type one error concludes that the results of the study were statistically significant when they’re not. Vice versa, a type two error concludes that the results are not statistically significant, but they are. Also, margin of error comes into play. P-value — a measure of deviation that determines which results are noteworthy — sets the stage for what is considered significant. Based on the method of a study, researchers can have stringent requirements for assessing the significance of a result (p≤.01), but most research uses p≤.05.
In simpler terms, p≤.05 allows researchers to be 95 percent certain that a result is meaningful. While the FDA used a p-value of <0.05, the researchers in the secondary study believe that the FDA failed to look at the statistical significance of the inter-related effects of BPA on multiple parts of the body, including the mammary glands, ovaries, kidneys, the prostate gland and cognitive-behavioral function.
Additionally, the statistical approaches the FDA sought to use would require hundreds of research replicates to be statistically valid. The FDA only had a budget to repeat the experiments up to 12 times per group, which some investigators questioned whether findings on these alone, especially with the methods the FDA sought to use, would provide meaningful results.
In 2012, the FDA banned the use of BPA in baby products, although that decision was largely due to public concern. However, the primary route of exposure to the effects of BPA are before babies are born. Since BPA is present in products used by pregnant mothers, it can lead to the development of health problems in babies including cancer later on in life.
The original statistical analysis for Rosenfeld’s portion of the project was done by Mark Ellersieck of MU, who has 30 years of experience, and a statistician with the FDA. When the analyses disagreed with each other, a neutral third-party was brought in to review the approaches used by Ellersieck and corroborated they were appropriate for the study design.
Now, Jiude Mao, a research scientist from the Division of Animal Sciences in Rosenfeld’s lab at Bond LSC, is working with Rosenfeld to reanalyze the results of the original study.
“I downloaded the raw data package online,” Mao said. “If you look at the effects of BPA on individual organs versus combining them and looking at its effects on multiple organs, the picture is very different.”
By using special informatics approaches, Mao found that the lowest dose of BPA tested simultaneously led to multiple effects on various target organs in females including the ovaries, uterus, mammary glands, heart, and fat tissue. In males, the prostate gland, along with the heart and adipose tissue showed inter-related changes due to BPA exposure.
Mao and Rosenfeld have also linked multi-organ effects of BPA at two other doses, with all doses tested currently considered safe by the FDA. They examined these inter-relationships at three age ranges: 21 days of age, 90-120 days of age, and 180 days of age. To the investigators’ knowledge this is the first type of toxicological study that has linked such data obtained in multiple investigators’ laboratories and shown such complex relationships.
The data from these three doses of BPA and three age ranges clearly indicate that BPA affects on a single organ can radiate out to affect many other organs throughout the body. By tugging on one organ, BPA can damage intricate webs that connects organs to each other. Such inter-relationships between individual CLARITY-BPA investigator data have not been considered by the FDA.
While a consensus hasn’t been met between the two parties, a potential solution for the data analysis discrepancy could be looking to machine learning or ‘deep learning’ to avoid human error or bias. This would include inputting both data sets into a program that can assess what the similarities and differences are and why the two groups are achieving different conclusions. This approach would ensure more confidence in the accuracy of the results instead of choosing a side to believe based on human calculations.
For the researchers, reevaluating the data means providing the full scope of the effects of BPA on multiple parts of the body. It also means giving consumers the correct information so that they can make well-informed decisions about their health.
“I am concerned that government agencies are not providing the public the fully story as to how BPA exposure might affect various organs, especially in infants exposed to this chemical during pre- and post-natal development when they do not have the full capacity to metabolize BPA and their organs are developing at this time,” Rosenfeld said.
Rosenfeld was joined by Jerrold Heindel, Scott Belcher, Jodi Flaws, Gail Prins, Shuk-Mei Ho, Juide Mao, Heather Patisaul, Ana Soto, Fred vom Saal and Thomas Zoeller from the Healthy Environmental and Endocrine Disruptor Strategies Commonweal, North Carolina State University, University of Illinois at Urbana-Champaign, University of Illinois at Chicago, University of Cincinnati College of Medicine, University of Missouri and University of Massachusetts at Amherst in this data reevaluation. Read more of their secondary results at the Journal of Reproductive Toxicology and see the original FDA CLARITY-BPA publication at FDA.gov.
Dong Xu, Bond LSC principal investigator and Shumaker Endowed Professor in the University of Missouri’s College of Engineering. | photo by Roger Meissen, Bond LSC
A Bond Life Sciences Center researcher has been inducted into an elite organization comprised of two percent of all medical and biological engineers.
The American Institution for Medical and Biological Engineering (AIMBE) this week announced the induction of Dong Xu, a Bond LSC principal investigator and Shumaker Endowed Professor in the University of Missouri’s College of Engineering.
“Election to the AIMBE College of Fellows is among the highest professional distinctions accorded to a medical and biological engineer,” said Kamrul Islam, chair of the college’s Electrical Engineering and Computer Science department.
Xu was selected for his “distinguished contributions to bioinformatics and computational biology, and extensive services to University of Missouri and his research community.”
In addition to his endowed faculty position, Xu serves as director of the Information Technology program, whose core facility is housed in Bond LSC.
Membership to AIMBE’s College of Fellows recognizes those who have made outstanding contributions to engineering and medicine research, practice or education, and to those pioneering new and developing fields.
Because of health concerns, AIMBE’s annual meeting and induction ceremony scheduled for this spring was canceled. Under special procedures, the induction was held remotely.
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.”
