Gary A. Weisman

#IAmScience Lucas Woods

March 22, 2019 By Mariah Cox in #IAmScience Tags: Sjögren’s Disease

By Mariah Cox | Bond LSC

Ten years ago, Lucas Woods stepped into Gary Weisman’s lab with a fresh perspective on P2 cell receptors. Now, as an experienced lab manager, Woods dives deeper into the role of these receptors in a myriad of diseases.

Woods came to the Bond Life Sciences Center after graduating from Missouri State University in Springfield with a degree in cell and molecular biology. He studied P2 receptors as a part of his undergraduate research with Dr. Richard Garrad, who completed his post-doctoral research in Weisman’s lab. Garrad recognized Woods’s interest in the area of study and recommended he continue his research with Weisman at MU.

“The initial plan was to work in Dr. Weisman’s lab for a year or two then enroll in graduate school, but after I started here, one thing led to another and here I am, 10 years later, still doing the same research I have been doing for the past 12 years,” Woods said.

Although Weisman’s lab researches the function of P2 receptors in diseases such as Alzheimer’s disease, autoimmune diseases and oral cancers, they are currently investigating the manipulation of P2 receptors in Sjögren’s syndrome.

Sjögren’s syndrome is an autoimmune disease primarily affecting women at later stages in life where the immune system attacks and damages the salivary and lacrimal glands, reducing the ability to produce saliva and tears. This can lead to dental caries, periodontitis, yeast and bacterial infections, digestive disorders, loss of taste and difficulty swallowing, all of which reduce the quality of life for patients. The progression of Sjögren’s syndrome can also lead to the development of lymphoma.

“Usually people don’t show up to the doctor until they notice they have dry mouth and dry eye,” Woods said. “There’s no real solution for them. There are current treatments that try to alleviate the symptoms, such as artificial saliva and tears, rather than treat the cause of the disease. The idea of this research is to make better treatments.”

Currently, Weisman’s lab is focusing on two drugs that target P2 receptors to systemically reduce the inflammation in the salivary gland and improve saliva flow. The lab uses mouse models of human Sjögren’s syndrome to test the effectiveness of these two drugs in blocking the response of P2 receptors to extracellular ATP, which can exacerbate inflammation if left unchecked.

Lucas Woods cultures human T cell line Jurkat cells. The lab uses the Jurkat cells to investigate the role of P2 receptors in T cell function. | photo by Mariah Cox, Bond LSC

“We were joking the other day that when people ask us what we do for a living and we say we collect mouse saliva, they don’t believe us,” Woods said.

Rather than trying to generate a specific drug for clinical use, the lab aims to establish the idea that if a safe drug is found that can block these receptors and improve the Sjögren’s-like symptoms in mice, then it may translate as a therapeutic strategy in humans.

After working with Weisman for 10 years, it’s safe to say Woods has learned a lot. But the main lesson that he has taken from his experience is that effective communication of science is key.

“Success in science is as much dependent on your ability to communicate science as your ability to do science,” Woods said. “That communication is often in the form of writing papers for publication or writing grants, but the ability to effectively communicate the work that you did and the work you are going to do is absolutely essential.”

In conjunction with his research, Woods is also taking classes toward completing a graduate degree.

“I’m in a unique position right now where I am both a research staff member in the biochemistry department and I’m a student in the department as well,” Woods said.

Woods’s interest in science sparked when he realized that it could lead to limitless discovery. The idea that he could be the first to discover something that the entire world doesn’t know about yet drives him in his research.

When not in the lab, Woods enjoys running and playing with his two kids, Audrey and Edison.

Eventually, Woods hopes to run his own lab. When asked whether he would continue his research with P2 receptors, Woods said it would be in his best interest because of his long history in the field of study.

“P2 receptors are so ubiquitous in the body, there’s no shortage of questions to ask that need answering,” Woods said.

Standing out through saliva

August 4, 2016 By Roger Meissen in Research Tags: Bond LSC, extracellular ATP, salivary glands, Sjogren's syndrome

Bond LSC scientist internationally recognized for work on salivary glands and autoimmune disorders

By Phillip Sitter | Bond LSC

You might not think too highly of spit, but you would quickly regret not having any.

People with Sjögren’s syndrome suffer chronic dry mouth and eyes from an overzealous immune system that attacks salivary and tear ducts, causing serious health issues.

Gary Weisman’s research might hold the key to understanding and managing this immune response, leading to effective treatment or even prevention of this ailment.

For this, the International Association of Dental Research, or IADR, awarded him the 2016 Distinguished Scientist Award for Salivary Research. Weisman accepted the award in June at the opening ceremonies of the IADR conference in Seoul, Republic of Korea.

Gary Weisman stands in his lab in Bond LSC where he studies the cellular mechanisms of auto-immune disease, specifically how the release of ATP from damaged cells signals receptors that trigger an immune response. | Phillip Sitter, Bond LSC

“We want the good, but not the bad,” said Weisman, a Bond Life Sciences Center investigator, of what we ideally want from our immune system’s functions.

Mice with un-checked autoimmune disease of their salivary glands have their glands destroyed. The disease can spread to other secretory organs next. An over-reactive immune system on a civil war-path can extend its damage to cause pancreatic failure and death.

The destruction wrought by Sjögren’s syndrome is self-inflicted, caused by an overreaction of our bodies’ defenses against infection and injury. This is what an autoimmune disease is.

But, our bodies’ immune cellular response team is complicated. Weisman said dozens of different cell types have been isolated and identified as part of the immune system, and he likens the immune system to fire, police and construction services in human society all working together.

While firefighters are meant to prevent further damage from an inferno, sometimes our bodies’ first responders start doing the equivalent of using dynamite to stop the spread of a fire.

In chronic inflammation, that autoimmune response can mean a burning, throbbing, constant pain. The key to a healthy immune response is balance. The balance has to be between containment and repair of damage caused by infection or injury and damage caused by chronic inflammation if that emergency response continues unabated.

Weisman has spent almost 30 years studying how to prevent our bodies’ immune system from over-reacting to threats and causing further harm.

Earlier in his career, Weisman studied how extracellular ATP plays a critical role in immune responses, and how too much of it can cause the over-reaction that leads to tissue destruction in autoimmune diseases. ATP, or adenosine 5’-triphosphate, is the main molecule used for energy in cellular activities inside cells. Weisman was one of the first scientists to study how damaged cells release ATP as a distress signal.

The released ATP signals receptors that “send out the alarm to the fire station” — the body’s immune cells, he said.

Once he understood this, Weisman began to manipulate the actions of released ATP to see how that would affect an immune response.

Mice with salivary gland autoimmune disease got healthy when the released ATP was prevented from activating their receptors on the surface of cells. Preventing the ATP receptors from being activated slowed down and even stopped the advance of autimmune disease.

Conversely, if you prevent the activation of the ATP receptors in lab mice with Alzheimer’s disease they die much more rapidly from the disease, Weisman said, suggesting that activation of immune cells by ATP is beneficial in slowing the progression of this disease.

Alzheimer’s disease and autoimmune diseases such as Sjögren’s syndrome are only some of the inflammatory diseases that Weisman has studied. With each of these diseases, the role of ATP receptors has to be investigated individually, suggesting that Weisman’s work may extend beyond salivary glands and the brain to other parts of the body.

“Our [ATP] receptor is also involved in heart disease,” Weisman said, and he added that other diseases like cystic fibrosis, cancer, lupus and arthritis have inflammatory components, too.

For now, we all fight a losing battle when it comes to our bodies’ management of the immune system. As we and our immune system age, it has the potential to destroy more than it protects and “eventually you could slip over to the dark side and die,” Weisman said.

In the meantime, Weisman said that a better understanding of the immune system could lead to more effective, targeted treatments of chronic inflammation and other autoimmune disorders. This could provide a new approach to control undesirable activation of the immune system beyond the use of with anti-histamines, anti-cytokines and ibuprofen.

Weisman is a Curator’s Distinguished Professor of Biochemistry. He began his salivary gland research at MU 27 years ago with Professor John Turner, before Turner’s retirement. Since then, his research has been continuously funded by the National Institutes of Health, where one of his recent grants was well scored and will likely be extended for another five years.

The Curious Case of Inflammation: One Lab’s Mission to Put the Pieces Together

May 11, 2015 By Paige Blankenbuehler in Research 18 Comments Tags: biochemistry, Bond LSC, gary weisman, inflammation, jean camden, laurie erb, lucas woods, weisman

White coat, dark room. Jean Camden, a senior technician in the Weisman lab, reviews salivary gland and brain tissue samples for research on inflammation. | Photo by Paige Blankenbuehler, Bond LSC

By Paige Blankenbuehler | MU Bond Life Sciences Center

There’s a criminal on the loose, striking every day. Millions fall victim, but there’s still no way to stop it. And, in all likelihood, you have been hurt by it.

If inflammation is an unsolved criminal case of the last three decades, then Gary Weisman has been the detective. He’s certain there’s an accomplice — perhaps many — that may be triggering the discomfort.

The Bond Life Sciences Center investigator is slowly revealing what makes inflammation tick and what makes it strike. Each epiphany brings another question. He’s certain there’s a way to prevent negative effects of unsolved inflammation.

Bond LSC investigator and MU professor of biochemistry, has been studying the ins-and-outs of inflammation for the last 30 years. | Photo by Paige Blankenbuehler, Bond LSC

Weisman has dedicated his career to understanding the micro-processes behind inflammation. He’s become so specialized that his techniques can be as hard to crack as the case itself.

“I would not ask anyone to explain what I do,” Weisman says. Nonetheless, he’s been able to divide the process of inflammation into two categories: components that repair the body and components that lead to its destruction. This will help find inflammation’s many accomplices to figure out why humans work, and what their bodies do when they don’t work so well.

“I am interested in the meaning of life,” Weisman says. “Life has become simpler for me because the scientific method carries everywhere. I’ve become aware of how simple we are as a machine.”

Criminal or just misunderstood?

Most criminals adopt patterns, but inflammation stands as a signpost for mysterious, underlying problems.

Its effects are usually localized: an arm, a joint, the brain or a gland. You feel a temperature spike then the skin reddens in a part of your body. Later still, the skin tightens and pain comes at a snail’s pace.

Not even cells are safe. Inflammation even strikes on the molecular level.

But really, inflammation can be a good thing. It’s part of the immune system’s bag of tricks to signal the body to bring in reinforcements to fight off the invasion. Normally, inflammation corrects a physical problem, but if it is not successful in repairing a problem, inflammation can become chronic and accelerate tissue destruction.

Just like in an episode of CSI, Weisman puts the pieces of the inflammation puzzle together in his office by applying the expertise of Laurie Erb, Jean Camden and Lucas Woods — all donned in white lab coats, eyes pressed to the microscope examining evidence and building molecular evidence in the case.

The MU associate professor of biochemistry and his team have become a sort of grant-wielding wizards to sustain his pursuit of inflammation triggers. National Institutes of Health grant awards have sustained his lab for decades. The funding has come from varied sources such as the MU Food for the 21^st Century Program, the Bond LSC, the Bright Focus Foundation, the American Heart Association and the Cystic Fibrosis Foundation. In recent years, research funding for Alzheimer’s disease and Sjogren’s syndrome (a disease of the salivary gland that causes dryness) have contributed, too.

But the funding source doesn’t matter because inflammation is the tie that binds.

Jean Camden processes samples under the Weisman lab's microscope. | Photo by Paige Blankenbuehler, Bond LSC — Jean Camden processes samples under the Weisman lab’s microscope. | Photo by Paige Blankenbuehler, Bond LSC

Advancements, like recent mapping of the human genome, have moved his work forward to understand inflammation’s complexity. Each experiment he completes fills in another blank slate in the “human owner’s manual.”

“As humans, we’re so intent on the fact that we’re superior to all, but really we’re not,” Weisman says. “With the Human Genome project, we’ve come to understand that all living things have similar designs … we are on the verge of finding revolutionary solutions to preventing or reversing human diseases.”

A receptor all our own

One specific player in the body’s immune system has kept Weisman’s attention for most of his career. The P2Y2 protein is a nucleotide receptor, and his lab team members affectionately refer to it as “our receptor.”

Nucleotide receptors are regulatory molecules in red blood cells. What they regulate is nuanced, mostly undetermined and of great interest to scientists. Answering that question has become Weisman’s wheelhouse.

The body manufactures 15 different types of nucleotide receptors, all similar in construction, but each are believed to have subtly different functional roles. It’s as if Weisman and his lab is on the case of a highly organized crime ring.

“Our receptor is mainly present when inflammation occurs, and we’re trying to figure out its role in a variety of diseases,” Weisman says.

The P2Y2 receptor has been observed in Alzheimer’s patients, along with a plaque build-up in the brain, and the receptor was suspected of playing a role in the disease’s progression.

Weisman and his colleagues found that the deletion of the P2Y2 receptor in a mouse model of Alzheimer’s disease accelerates progression of plaque build-up, neurological symptoms and death. This suggests that the receptor has anti-inflammatory effects rather than being “guilty by association” with the tissue-destructive aspects of inflammation.

“It’s like I have this 30,000-piece jigsaw puzzle in front of me that I have to put together,” Weisman says. “What’s the difference between you and me? As a machine, surprisingly very little.”

This simplicity drives Weisman to continue solving the mysteries of inflammation and search for its underlying chemical processes. By understanding the body’s chemical reactions, he believes treatments can be developed to focus the immune system on repairing damaged tissues.

Through studying his receptor, Weisman is breaking up inflammation’s crime ring.