Why self-defense turns self-attack

By Jinghong Chen | Bond Life Sciences Center

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Mahmoud Khalafalla, a Ph.D. student at Weisman’s lab, is isolating RNA from salivary glands of Sjögren’s syndrome mouse model to look for the expression of pro-inflammatory genes. | photo by Jinghong Chen, Bond LSC

Our immune system is often the key to our health. Everyday, it works to protect us from foreign invaders such as bacteria and virus, but what happens when it attacks our own tissues?

Gary Weisman, a Curator’s Distinguished Professor of Biochemistry at the Bond Life Sciences Center, is working to advance our understanding of the mechanisms behind immune system function and autoimmune diseases such as Sjögren’s syndrome.

In our immune system, B cells are responsible for producing antibodies to recognize foreign invaders. However, in many autoimmune diseases, B cells produce autoantibodies that recognize our own proteins, causing inflammation and tissue damage. In Sjögren’s syndrome (SS), they attack the glands that produce saliva and tears.

Patients with SS often suffer chronic dry eyes and dry mouth, which might lead to bacterial infection, difficulties in swallowing and speech.

“The symptoms decrease the quality of life rather than the length of life,” said Lucas Woods, research lab manager in Weisman’s lab.

Although SS patients are at higher risk of developing lymphoma cancers and other concurrent autoimmune diseases that may increase mortality, Woods further explained.

According to the Sjögren’s Syndrome Foundation, there are an estimated four million people living with the disease in the U.S. For unknown reasons, 90 percent of them are female.

Yet, current clinical treatments only reduce symptoms by using artificial saliva and tears or cholinergic agents to promote fluid secretion, but there is no approved treatment to reduce the inflammation of the glands themselves. This is the focus of Weisman’s lab.

Sensor of danger

There are 15 different types of nucleotide receptors in humans that regulate numerous cell processes from inflammatory responses to tissue regeneration. Those receptors are stimulated by nucleotides such as ATP. In the past three and a half years, Mahmoud Khalafalla, a Ph.D. student in Weisman’s lab, has focused on one of them in particular – the P2X7 receptor.

Previous studies show increased P2X7 expression in salivary glands from SS patients, as compared to healthy individuals. To understand the reasons behind this, Weisman’s lab used genetically modified mice that develop disease traits similar to SS patients.

In this mouse model, Sjögren’s-like disease occurs when the immune cells invade salivary glands and damage the tissue, leading to decreased saliva production. The invasion of immune cells is triggered by proinflammatory cytokines, a type of signaling molecule that promotes the recruitment of immune cells to the inflamed areas.

But what induces those cytokines?

Weisman’s lab tries to piece together the answer. For the first time, they found that the P2X7 receptor is responsible for the release of these proinflammatory molecules from salivary gland epithelial cells.

To function, most cell-surface receptors require ligands that bind to the receptor to induce cellular responses. The ligand for the P2X7 receptor is ATP – the “energy currency inside of cells.” P2X7 receptors are activated when high concentrations of ATP are released to the outside of the cells, which typically occurs when the cells are injured during inflammation.

“P2X7 receptors [act like] the sensor of danger,” Khalafalla said.

After identifying the role of the P2X7 receptor, the lab then asked: if we stop its activation, what would happen?

Using a drug that inhibits P2X7 receptor activation, they blocked the receptor in their SS mouse model to determine its effect on the development of autoimmune disease. Interestingly, saliva secretion was restored when the P2X7 receptor is blocked while the levels of invading immune cells in salivary glands were dramatically reduced.

“This gives us the thought that [blockade of the] P2X7 receptor is really a promising strategy to reduce salivary inflammation. This may not only relate to Sjögren’s syndrome, but to other autoimmune diseases as well,” Khalafalla said.

Our receptor

Another similar receptor that plays a role in autoimmune diseases is the P2Y2 receptor, which has been referred to as “our receptor” by Weisman’s lab.

As one of the researchers who proved the existence of this receptor, Weisman has spent most of his career studying it.

One of his research projects investigating P2Y2 receptors in human disease recently gained a grant extension for another five years from the National Institutes of Health. The lab found that in a mouse model of SS, similar to the P2X7 receptor, the expression of P2Y2 receptors was increased in both the salivary gland epithelial cells and immune cells.

Furthermore, after they knocked out the P2Y2 receptor in the SS mouse model by breeding them with genetically-modified P2Y2 receptor knockout mice, the inflammation of salivary glands was dramatically reduced.

“The very next step is that we are going to isolate these immune cells out of the diseased mouse salivary glands, and characterize what kinds of cells they are. We want to know exactly which ones are controlling the development of autoimmune diseases, and how P2Y2 receptors and nucleotides like ATP in general are contributing to the diseases,” Woods said.

 

Gary Weisman is a Curator’s Distinguished Professor of Biochemistry at the Bond Life Sciences Center. His research focuses on the relationship between inflammatory diseases and nucleotide receptors. He currently works on a collaborative research project with Dr. Carisa Petris, an eye surgeon at the MU Hospital, to understand the mechanism of how Sjögren’s syndrome damages the tear-secreting lacrimal glands in mice.

 

Marc Johnson #IAmScience

Marc Johnson

Marc Johnson, a virology professor at Bond LSC. | photo by Morgan McOlash, Bond LSC

By Mary Jane Rogers | Bond LSC

“#IAmScience because the mysteries of the natural world aren’t going to solve themselves.”

Since the third grade, Marc Johnson never wanted to be anything else but a mad scientist. What began as experimenting with sprouting seeds and chemistry sets has blossomed into a career in virology. Specifically, he studies the “moves and countermoves” of viral components, a few hundred thousand at time! His advice for people wondering if science is for them: “If you’ve ever stayed up until 4 in the morning to finish a puzzle, you might be a scientist.”

Harvard researcher to speak at Life Sciences Week

Jessica Whited studies the genetics behind how salamanders grow severed limbs

By Eleanor Hasenbeck | Bond LSC

axolotl Ruben

An axolotl rests at the bottom of its tank at Menagerie du Jardin des Plantes in Paris. | photo by Jack Baker, Flickr

It takes about two months for an axolotl to regenerate a lost limb. Humans, as you probably know, don’t regenerate limbs.

But, a basic understanding of how the Mexican salamander regrows limbs advance regenerative medicine in humans according to Jessica Whited, a researcher at Brigham Women’s Hospital and assistant professor at Harvard Medical School.

Whited will speak at 3:30 p.m., Thursday April 13, in Monsanto Auditorium as part of Missouri Life Sciences Week at Bond Life Science Center. Her lecture, “Identifying roadblocks to regeneration in axolotl salamanders” will present the lab’s discoveries and evidence that a specific gene in axolotls can block the animal’s ability to regenerate.

Whited’s lab found axolotls can exhaust their ability to regenerate. When a limb is severed repeatedly, the salamander stops producing blastemas, the mass of cells capable of regeneration that allow the limb to grow back. This could be due to a dysregulated gene blocking the animal’s ability to produce them.

The Whited Lab sequenced the mRNA in axolotls that could regenerate limbs and that could no longer regenerate. They found 912 genes that differed between the two groups. Whited will discuss one of these genes, which her lab considers a potential inhibitor to regeneration.

“It’s much more common for people to think “Oh, what are the things that promote limb regeneration?’ than it is to think about the things that we might have to block to make it happen,” Whited said. “This project has the potential to uncover the roadblocks, which could turn out to be equally critical.”

An MU alumna, Whited received the National Institutes of Health New Innovator Award in 2015 for her work with this unique regenerative salamander. She earned a PhD in biology at the Massachusetts Institute of Technology, and two undergraduate degrees in biological sciences and philosophy at MU.

Whited attended MU as a Bright Flight and Curator’s Scholar. And though it happened nearly 20 years ago, she said receiving those two scholarships were among the most important things that happened in her career. As a high school student, she knew she would go to college, but financially, she didn’t know how it would happen. She also credits her education and undergraduate research experience at MU for preparing her to think at the research bench.

“You have to get an undergraduate education, and it totally prepared me even for graduate school at MIT, which is one of the top programs in the world, in many subjects, but in biology especially,” Whited said. “The idea that you could find a career where you’re using your brain as your primary asset, I figured that out while I was at the University of Missouri, because there were people, our professors, doing that.”

Whited’s lecture is free and open to the public as part of Missouri Life Sciences Week. It occurs at 3:30 on Thursday, April 13 in Bond LSC’s Monsanto Auditorium. See more about events during the week at bondlsc.missouri.edu/life-sciences-week.

Planting a seed for sciences

Jinghong Chen | Bond Life Sciences Center

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Plants on the left grow with rhizobia bacteria, one type of fixing nitrogen bacteria, in the greenhouse, while the plants on the right grow without the bacteria. | photo by Jinghong Chen, Bond LSC

Since eight years old, Beverly Agtuca knew she wanted to be a scientist.

A trip to Philippines changed Agtuca, an American-born Filipino, and inspired her passion on plants.

“My grandma always told me to work in the field all day so that they can have enough food for us to eat,” Agtuca said. “The life [in Philippines] is so different from here…I want to not just provide food but be that scientist trying to figuring something out, and hopefully saving the world.”

Agtuca is on her way to her dream. She is now a third year doctoral student in Gary Stacey’s lab at Bond Life Sciences Center with a focus on nitrogen-fixing bacteria.

Although she has been involved in research since high school, Agtuca recently faced a new challenge of telling people about her work. The Preparing Tomorrow’s Leaders of Science class tasked her with making a 90-second video to explain her two-year study to the general public.

Her team, “The A Team,” chose to go with the benefits of having nitrogen-fixing bacteria.

For decades, people have been adding nitrogen fertilizers to plants to improve yields, but this can lead to pollution in water systems and ecosystems. Scientists need to enhance plant productivity to meet a huge food demand by the year of 2050.

One little bacteria might make this possible and save the world. Rhizobia, a type of natural bacteria in soil, are able to fix nitrogen via biological nitrogen fixation. These bacteria can convert nitrogen gas into ammonia as a plant nutrient source, while the plants give all the carbon sources back to the bacteria.

“It is like a walky-talky,” Agtuca said. “They are communicating with each other.”

Yet before speaking to the public, Agtuca needs to explain the plant-bacteria interaction to her teammates. Students less well versed in science like Jessica Kaiser, a strategic communication student, thinks of science differently.

“The biggest issue we ran into is jargon, like basic science words that [my teammates] are so comfortable with,” Kaiser said. “We need to focus on what people care about instead of the technical sides, to focus on why it matters to anybody rather than just to a science person.”

Within two weeks, they produced the video “Good Microbes: reducing pollution one farm at a time.” Along with two other teams, their videos will be commented and judged by representatives from Monsanto.

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“The A Team” stands together at Bond Life Sciences Center. From left to right: Jessica Kaiser, Sven Nelson, Anna Glowinski, Eleni Galata and Beverly Agtuca. | photo by Jinghong Chen, Bond LSC

The 90-second video is just a glimpse of Agtuca’s study. In the last two years she has been focusing on the use of a new technique — laser ablation electrospray ionization mass spectrometry (LAESI-MS) — that does in situ metabolic profiling of tissues. The lab is using LAESI-MS to investigate the metabolites in a well-characterized model plant-rhizobium system, specifically nitrogen-fixing soybean nodules resulting from root infection by the symbiotic bacterium Bradyrhizobium japonicum.

This work includes a huge collaboration that was developed through a Department of Energy (DOE) grant involving the George Washington University, Washington D.C. and the Environmental Molecular Science Laboratory (EMSL), Pacific Northwest National Laboratory, Richland, WA.

LAESI-MS works like a superhero’s laser-like beams. You first aim the laser on the sample, which then heats it and causes neutral particles to be released into the air. This plume of neutrals is then captured and ionized by the electrospray, and finally analyzed by the spectrometer to figure out the exactly what metabolites in nodules are involved in biological nitrogen fixation.

“It takes about three seconds to analyze one sample using this LAESI-MS technique,” Agtuca said. Other metabolic techniques require extensive pre-treatment of the sample before analysis.

By analyzing the data collected via LAESI-MS, the lab is able to confirm that future plant studies could apply this new approach to understand the interactions between plant and bacteria.

Agtuca’s research is a long way from her first experiences with plants. She still remembers the moment she found her plants in her own garden died. She was less than 10 years old, yet devoted to taking care of her plants with water and fertilizers.

“I was really sad. I could not get my tomatoes, peppers and eggplants to live.…That makes me think that I want to answer why they didn’t grow,” Agtuca said.

More than ever, her future is helping her answer those question for herself.

 

Gary Stacey is a Bond LSC investigator and MU curators’ professor of plant science and MSMC endowed professor of soybean biotechnology. Read more here about Stacey lab.

Sven Nelson is a USDA/ARS postdoctoral research scientist at the University of Missouri. Anna Glowinski is a Ph.D. student in the USDA/ARS lab. Jessica Kaiser is a graduate student in strategic communication. Eleni Galata works as the team mentor and she is a Ph.D. student in agricultural and applied economics at MU.

Lloyd Sumner #IAmScience

Lloyd Sumner

Lloyd Sumner, biochemistry professor and Director of the Metabolomics Center at Bond LSC. | photo by Morgan McOlash, Bond LSC

By Mary Jane Rogers | Bond LSC

“#IAmScience because I have an infinite curiosity and we have some powerful toolsets that I am confident will make a difference, not just in plant biochemistry, but in many scientific arenas.”

What change you would like to see in this world because of your research?

“I’m a technology junkie at heart. We are developing tools that can potentially advance many areas, and not just my own personal research program. I want to continue to build upon these tools and also apply them in a meaningful manner. On the plant side, I want to discover and characterize many new biochemical pathways, and use this information to make stronger, healthier and more productive plants. I also want to apply these cutting-edge tools to an ever expanding set of problems; i.e. cancer, veterinary medicine, nutrition, etc. I’m confident that every day when I get up, by the end of that day, week or month that we are making that difference.” -Lloyd Sumner

Scott Peck #IAmScience

Scott Peck

Scott Peck, a biochemistry professor at Bond LSC. | photo by Morgan McOlash, Bond LSC

By Mary Jane Rogers | Bond LSC

“#IAmScience because I want to discover. I want to ‘see’ – by understanding – things that others haven’t ‘seen’ before.”

Every day we make decisions based off on what we encounter in the environment. Plants do the same thing. Scott Peck, a Chicago-area native, is a biochemist who studies how plants translate information they receive about the environment (such as changes in light and temperature) into their own chemical “decisions”, also known as signal transduction. For him, it’s about making biology into a puzzle. Put the right pieces together, and you find ways to create more resistant crops or more effective antibiotics. With today’s technology and Peck’s passion for plant communication, anything could be possible.